In the US, Vivactil (protriptyline systemic) is a member of the drug class tricyclic antidepressants and is used to treat Depression.
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VFEND 50 mg and 200 mg film-coated tablets.
VFEND 200 mg powder for solution for infusion.
VFEND 40 mg/ml powder for oral suspension.
Film-coated tablets:
Each tablet contains 50 mg or 200 mg voriconazole.
Excipient: lactose monohydrate 63.42 mg or 253.675 mg
For a full list of excipients, see section 6.1.
Powder for solution for infusion:
Each ml contains 10 mg of voriconazole after reconstitution (see section 6.6) - once reconstituted further dilution is required before administration. Each vial contains 200 mg of voriconazole.
Excipient: each vial contains 217.6 mg sodium
For a full list of excipients, see section 6.1.
Powder for oral suspension:
Each ml of oral suspension contains 40 mg of voriconazole when reconstituted with water (see section 6.6). Each bottle contains 3 g of voriconazole.
Excipient: Each ml of suspension contains 0.54 g of sucrose
For a full list of excipients, see section 6.1.
Film-coated tablets:
White to off-white, round tablets, debossed “Pfizer” on one side and “VOR50” on the reverse.
White to off-white, capsule-shaped tablets, debossed “Pfizer” on one side and “VOR200” on the reverse.
Powder for solution for infusion:
White lypophilised powder
Powder for oral suspension:
White to off-white powder
Voriconazole, is a broad spectrum, triazole antifungal agent and is indicated as follows:
• Treatment of invasive aspergillosis.
• Treatment of candidaemia in non-neutropenic patients
• Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei).
• Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp.
VFEND should be administered primarily to patients with progressive, possibly life-threatening infections.
Film-coated tablets (50mg and 200mg):
VFEND film-coated tablets are to be taken at least one hour before, or one hour following, a meal.
Powder for oral suspension:
VFEND oral suspension (40mg/mL) is to be taken at least one hour before, or two hours following, a meal.
Powder for solution for infusion:
VFEND requires reconstitution and dilution (see section 6.6) prior to administration as an intravenous infusion. Not for bolus injection.
It is recommended that VFEND is administered at a maximum rate of 3 mg/kg per hour over 1 to 2 hours.
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.4).
VFEND must not be infused into the same line or cannula concomitantly with other intravenous products. VFEND must not be administered simultaneously with any blood product or any short-term infusion of concentrated solutions of electrolytes, even if the two infusions are running in separate lines. Total parenteral nutrition (TPN) need not be discontinued when prescribed with VFEND, but does need to be infused through a separate line (see section 6.2).
Use in adults and adolescents (12 to 16 years of age)
Therapy must be initiated with the specified loading dose regimen of either intravenous or oral VFEND to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of the high oral bioavailability (96 %; see section 5.2), switching between intravenous and oral administration is appropriate when clinically indicated.
Detailed information on dosage recommendations is provided in the following table:
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Dosage adjustment
Film-coated tablets & Powder for oral suspension:
If patient response is inadequate, the maintenance dose may be increased to 300 mg twice daily for oral administration. For patients less than 40 kg the oral dose may be increased to 150 mg twice daily.
If patients are unable to tolerate treatment at these higher doses reduce the oral dose by 50 mg steps to the 200 mg twice daily (or 100 mg twice daily for patients less than 40 kg) maintenance dose.
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see sections 4.4 and 4.5.
Rifabutin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see sections 4.4 and 4.5.
Efavirenz may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see sections 4.4 and 4.5).
Treatment should be as short as possible depending on the patients' clinical and mycological response.
For long term treatment greater than 6 months, a careful assessment of the benefit-risk balance should be considered. See section 4.4 Special warnings and precautions for use (Dermatological adverse events) and section 5.1 Pharmacodynamic properties (Duration of treatment).
Powder for solution for infusion:
If patients are unable to tolerate treatment at 4 mg/kg twice daily, reduce the intravenous dose to 3 mg/kg twice daily.
Rifabutin or phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously twice daily, see sections 4.4 and 4.5.
Efavirenz may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see sections 4.4 and 4.5).
Treatment duration should be as short as possible depending on the patients' clinical and mycological response.
The duration of treatment with the intravenous formulation should be no longer than 6 months. See section 5.3 (preclinical safety data). For voriconazole in general, long term treatment greater than 6 months requires careful assessment of the benefit-risk balance. See section 4.4 Special warnings and precautions for use (Dermatological adverse events), section 5.1 Pharmacodynamic properties (Duration of treatment).
Use in the elderly
No dose adjustment is necessary for elderly patients (see section 5.2).
Use in patients with renal impairment
Film-coated tablets & Powder for oral suspension:
The pharmacokinetics of orally administered voriconazole are not affected by renal impairment. Therefore, no adjustment is necessary for oral dosing for patients with mild to severe renal impairment (see section 5.2).
Voriconazole is haemodialysed with a clearance of 121 ml/min. A four hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
Powder for solution for infusion:
In patients with moderate to severe renal dysfunction (creatinine clearance < 50 ml/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy (see section 5.2).
Voriconazole is haemodialysed with a clearance of 121 ml/min. A 4 hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min.
Use in patients with hepatic impairment
No dose adjustment is necessary in patients with acute hepatic injury, manifested by elevated liver function tests (ALAT, ASAT) (but continued monitoring of liver function tests for further elevations is recommended).
It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving VFEND (see section 5.2).
VFEND has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).
VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity (see also section 4.8).
Use in children
VFEND is not recommended for use in children below 2 years due to insufficient data on safety and efficacy (see also sections 4.8 and 5.1).
Film-coated tablets, Powder for oral suspension & Powder for solution for infusion:
The recommended maintenance dosing regimen in paediatric patients aged 2 to <12 years is as follows:
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*Based on a population pharmacokinetic analysis in 82 immunocompromised patients aged 2 to <12 years
**Based on a population pharmacokinetic analysis in 47 immunocompromised patients aged 2 to <12 years
Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see section 4.8 and section 5.2).
Adolescents (12 to 16 years of age): should be dosed as adults.
Film-coated tablets and Powder for oral suspension:
These paediatric dose recommendations are based on studies in which VFEND was administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric transit time in paediatrics, the absorption of the tablets may be different in paediatric compared to adult patients. It is therefore recommended to use the oral suspension formulation in children aged 2 to <12 years.
Powder for solution for infusion:
If paediatric patients are unable to tolerate an intravenous dose of 7mg/kg twice daily, a dose reduction from 7mg/kg to 4mg/kg twice daily may be considered based on the population pharmacokinetic analysis and previous clinical experience. This provides equivalent exposure to 3mg/kg twice daily in adults (see section 4.2 use in adults).
Hypersensitivity to the active substance or to any of the excipients.
Co-administration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine with VFEND is contraindicated since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.5).
Co-administration of VFEND with rifampicin, carbamazepine and phenobarbital is contraindicated since these medicinal products are likely to decrease plasma voriconazole concentrations significantly (see section 4.5).
Co-administration of VFEND with high dose ritonavir (400 mg and above twice daily) is contraindicated because ritonavir significantly decreases plasma voriconazole concentrations in healthy subjects at this dose. (see section 4.5, for lower doses see section 4.4).
Co-administration of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, is contraindicated since increased plasma concentrations of these medicinal products can lead to ergotism (see section 4.5).
Co-administration of voriconazole and sirolimus is contraindicated, since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see section 4.5).
The concomitant use of voriconazole with St John's Wort is contraindicated (see section 4.5).
Hypersensitivity: Caution should be used in prescribing VFEND to patients with hypersensitivity to other azoles (see also section 4.8).
Duration of IV treatment: The duration of treatment with the intravenous formulation should be no longer than 6 months. See section 5.3 (Preclinical safety data).
Cardiovascular:
Some azoles, including voriconazole have been associated with QT interval prolongation. There have been rare cases of torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medications that may have been contributory. Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as
• Congenital or acquired QT-prolongation
• Cardiomyopathy, in particular when heart failure is present
• Sinus bradycardia
• Existing symptomatic arrhythmias
• Concomitant medication that is known to prolong QT interval.
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.2). A study has been conducted in healthy volunteers which examined the effect on QT interval of single doses of voriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec (see section 5.1).
Infusion-related reactions: Infusion-related reactions, predominantly flushing and nausea, have been observed during administration of the intravenous formulation of voriconazole. Depending on the severity of symptoms, consideration should be given to stopping treatment (see section 4.8).
Hepatic toxicity: In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with VFEND (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly haematological malignancy). Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy (see section 4.8).
Monitoring of hepatic function: Monitoring of hepatic function should be carried out in both children and adults. Patients at the beginning of therapy with voriconazole and patients who develop abnormal liver function tests during VFEND therapy must be routinely monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of VFEND should be considered if clinical signs and symptoms are consistent with liver disease development. Monitoring of hepatic function should be carried out in both children and adults.
Visual adverse events: There have been rare reports of prolonged visual adverse events, including blurred vision, optic neuritis and papilloedema (see section 4.8).
Renal adverse events: Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function (see section 4.8).
Monitoring of renal function: Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Monitoring of pancreatic function: Patients, especially children, with risk factors for acute pancreatitis (e.g. recent chemotherapy, hematopoietic stem cell transplantation (HSCT)), should be monitored closely during Vfend treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.
Dermatological adverse events: Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with VFEND. If patients develop a rash they should be monitored closely and VFEND discontinued if lesions progress.
In addition VFEND has been associated with phototoxicity and pseudoporphyria. It is recommended that patients avoid intense or prolonged exposure to direct sunlight during VFEND treatment and use measures such as protective clothing and sunscreen when appropriate. In patients with phototoxicity and additional risk factors, including immunosuppression, squamous cell carcinoma of the skin has been reported during long-term therapy. Physicians should therefore consider the need to limit the exposure to VFEND (see Section 4.2 (Posology and method of administration) and Section 5.1 Pharmacodynamic properties (Duration of treatment). If a patient develops a skin lesion consistent with squamous cell carcinoma, VFEND discontinuation should be considered.
Paediatric use: Safety and effectiveness in paediatric subjects below the age of two years has not been established (see also sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in paediatric patients aged 2 to <12 years with malabsorption and very low body weight for age. In that case, intravenous voriconazole administration is recommended.
Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Careful monitoring of phenytoin levels is recommended when phenytoin is co-administered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk (see section 4.5).
Rifabutin (CYP450 inducer): Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g. uveitis) is recommended when rifabutin is co-administered with voriconazole. Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk (see section 4.5).
Methadone (CYP3A4 substrate). Frequent monitoring for adverse events and toxicity related to methadone, including QTc prolongation, is recommended when co-administered with voriconazole since methadone levels increased following co-administration of voriconazole. Dose reduction of methadone may be needed (see section 4.5).
Short Acting Opiates (CYP3A4 substrate): Reduction in the dose of alfentanil, fentanyl and other short acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g. sufentanil) should be considered when co-administered with voriconazole (see section 4.5). As the half-life of alfentanil is prolonged in a four-fold manner when alfentanil is co-administered with voriconazole and in an independent published study, concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC 0-frequent monitoring for opiate-associated adverse events (including a longer respiratory monitoring period) may be necessary.
Long Acting Opiates (CYP3A4 substrate): Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 (e.g., hydrocodone) should be considered when coadministered with voriconazole. Frequent monitoring for opiate-associated adverse events may be necessary (see Section 4.5).
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUC
Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): Co-administration of voriconazole and low dose ritonavir (100mg twice daily) should be avoided unless an assessment of the benefit/risk justifies the use of voriconazole. (see section 4.5, for higher doses see section 4.3).
Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate): When voriconazole is co-administered with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and that of efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2 and 4.5).
VFEND tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
VFEND oral suspension contains sucrose and should not be given to patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase deficiency or glucose-galactose malabsorption.
Sodium content: Each vial of VFEND powder for infusion contains 217.6 mg of sodium. This should be taken into consideration for patients on a controlled sodium diet.
Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily. These results are relevant to other populations and routes of administration.
This section addresses the effects of other medicinal products on voriconazole, the effects of voriconazole on other medicinal products and two-way interactions. The interactions for the first two sections are presented in the following order: contraindications, those requiring dosage adjustment and careful clinical and/or biological monitoring and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.
Effects of other medicinal products on voriconazole
Voriconazole is metabolised by cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations respectively.
Rifampicin (CYP450 inducer): Rifampicin (600 mg once daily) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve within a dose interval) of voriconazole by 93 % and 96 %, respectively. Co-administration of voriconazole and rifampicin is contraindicated (see section 4.3).
Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): The effect of the co-administration of oral voriconazole (200 mg twice daily) and high dose (400 mg) and low dose (100 mg) oral ritonavir was investigated in two separate studies in healthy volunteers. High doses of ritonavir (400 mg twice daily) decreased the steady state Cmax and AUC of oral voriconazole by an average of 66 % and 82 %, , whereas low doses of ritonavir (100mg twice daily) decreased the Cmax and AUC of voriconazole by an average of 24 % and 39 % respectively. Administration of voriconazole did not have a significant effect on mean Cmax and AUC of ritonavir in the high dose study, although a minor decrease in steady state Cmax and AUC of ritonavir with an average of 25 % and 13 % respectively was observed in the low dose ritonavir interaction study. One outlier subject with raised voriconazole levels was identified in each of the ritonavir interaction studies. Co-administration of voriconazole and high doses of ritonavir (400 mg and above twice daily) is contraindicated. Co-administration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see section 4.3 and 4.4).
Carbamazepine and phenobarbital (potent CYP450 inducers): Although not studied, carbamazepine or phenobarbital are likely to significantly decrease plasma voriconazole concentrations. Co-administration of voriconazole with carbamazepine and phenobarbital is contraindicated (see section 4.3).
Cimetidine (non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg twice daily) increased voriconazole Cmax and AUC by 18 % and 23 %, respectively. No dosage adjustment of voriconazole is recommended.
Ranitidine (increases gastric pH): Ranitidine (150 mg twice daily) had no significant effect on voriconazole Cmax and AUC.
Macrolide antibiotics: Erythromycin (CYP3A4 inhibitor; 1 g twice daily) and azithromycin (500 mg once daily) had no significant effect on voriconazole Cmax and AUC.
St John's Wort (CYP450 inducer; P-gp inducer): In a clinical study in healthy volunteers, St John's Wort exhibited a short initial inhibitory effect followed by induction of voriconazole metabolism. After 15 days of treatment with St John's Wort (300 mg three times daily), plasma exposure following a single 400 mg dose of voriconazole decreased by 40-60%. Therefore, concomitant use of voriconazole with St John's Wort is contraindicated (see section 4.3).
Effects of voriconazole on other medicinal products
Voriconazole inhibits the activity of cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. Therefore there is potential for voriconazole to increase the plasma levels of substances metabolised by these CYP450 isoenzymes.
Voriconazole should be administered with caution in patients with concomitant medication that is known to prolong QT interval. When there is also a potential for voriconazole to increase the plasma levels of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide) co-administration is contraindicated (see below and section 4.3)
Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates): Although not studied, co-administration of voriconazole with terfenadine, astemizole, cisapride, pimozide, or quinidine is contraindicated, since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).
Sirolimus (CYP3A4 substrate): Voriconazole increased sirolimus (2 mg single dose) Cmax and AUC by 556 % and 1014 %, respectively. Co-administration of voriconazole and sirolimus is contraindicated (see section 4.3).
Ergot alkaloids (CYP3A4 substrates): Although not studied, voriconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism. Co-administration of voriconazole with ergot alkaloids is contraindicated (see section 4.3).
Cyclosporin (CYP3A4 substrate): In stable, renal transplant recipients, voriconazole increased cyclosporin Cmax and AUC by at least 13 % and 70 %, respectively. When initiating voriconazole in patients already receiving cyclosporin it is recommended that the cyclosporin dose be halved and cyclosporin level carefully monitored. Increased cyclosporin levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporin levels must be carefully monitored and the dose increased as necessary.
Methadone (CYP3A4 substrate): In subjects receiving a methadone maintenance dose (32-100 mg once daily) co-administration of oral voriconazole (400 mg twice daily for 1 day, then 200 mg twice daily for four days) increased the Cmax and AUC of pharmacologically active R-methadone by 31 % and 47 %, respectively, whereas the Cmax and AUC of the S-enantiomer increased by approximately 65 % and 103 %, respectively. Voriconazole plasma concentrations during co-administration of methadone were comparable to voriconazole levels (historical data) in healthy subjects without any comedication. Frequent monitoring for adverse events and toxicity related to increased plasma concentrations of methadone, including QT prolongation, is recommended during co-administration. Dose reduction of methadone may be needed.
Short Acting Opiates (CYP3A4 substrate): Steady-state administration of oral voriconazole increased the AUC
Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of voriconazole (400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC 0-
Long Acting Opiates (CYP3A4 substrate): In an independent published study, coadministration of multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200 mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean Cmax and AUC0–
Tacrolimus (CYP3A4 substrate): Voriconazole increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCt (area under the plasma concentration time curve to the last quantifiable measurement) by 117 % and 221 %, respectively. When initiating voriconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to a third of the original dose and tacrolimus level carefully monitored. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels must be carefully monitored and the dose increased as necessary.
Oral anticoagulants:
Warfarin (CYP2C9 substrate): Co-administration of voriconazole (300 mg twice daily) with warfarin (30 mg single dose) increased maximum prothrombin time by 93 %. Close monitoring of prothrombin time is recommended if warfarin and voriconazole are co-administered.
Other oral anticoagulants e.g. phenprocoumon, acenocoumarol (CYP2C9, CYP3A4 substrates): Although not studied, voriconazole may increase the plasma concentrations of coumarins and therefore may cause an increase in prothrombin time. If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Sulphonylureas (CYP2C9 substrates): Although not studied, voriconazole may increase the plasma levels of sulphonylureas, (e.g. tolbutamide, glipizide, and glyburide) and therefore cause hypoglycaemia. Careful monitoring of blood glucose is recommended during co-administration.
Statins (CYP3A4 substrates): Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase plasma levels of statins that are metabolised by CYP3A4. It is recommended that dose adjustment of the statin be considered during co-administration. Increased statin levels have been associated with rhabdomyolysis.
Benzodiazepines (CYP3A4 substrates): Although not studied clinically, voriconazole has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma levels of benzodiazepines that are metabolised by CYP3A4 (e.g. midazolam and triazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during co-administration.
Vinca Alkaloids (CYP3A4 substrates): Although not studied, voriconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity.
Prednisolone (CYP3A4 substrate): Voriconazole increased Cmax and AUC of prednisolone (60 mg single dose) by 11 % and 34 %, respectively. No dosage adjustment is recommended.
Digoxin (P-glycoprotein mediated transport): Voriconazole had no significant effect on Cmax and AUC of digoxin (0.25 mg once daily).
Mycophenolic acid (UDP-glucuronyl transferase substrate): Voriconazole had no effect on the Cmax and AUCt of mycophenolic acid (1 g single dose).
Non-Steroidal Anti-Inflammatory Drugs (CYP2C9 substrates): Voriconazole increased Cmax and AUC of ibuprofen (400 mg single dose) by 20% and 100%, respectively. Voriconazole increased Cmax and AUC of diclofenac (50 mg single dose) by 114% and 78%, respectively. Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.
Two-way interactions
Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk.
Phenytoin (300 mg once daily) decreased the Cmax and AUC of voriconazole by 49 % and 69 %, respectively. Voriconazole (400 mg twice daily, see section 4.2) increased Cmax and AUCof phenytoin (300 mg once daily) by 67 % and 81 %, respectively. Careful monitoring of phenytoin plasma levels is recommended when phenytoin is co-administered with voriconazole.
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg /kg intravenously twice daily or from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see section 4.2.
Rifabutin (CYP450 inducer): Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk.
Rifabutin (300 mg once daily) decreased the Cmax and AUCof voriconazole at 200 mg twice daily by 69 % and 78 %, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96 % and 68 % of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUCwere 104 % and 87 % higher, respectively, compared with voriconazole alone at 200 mg twice daily. Voriconazole at 400 mg twice daily increased Cmax and AUCof rifabutin by 195 % and 331 %, respectively.
If rifabutin co-administration with voriconazole is justified then the maintenance dose of voriconazole may be increased to 5 mg/kg intravenously twice daily or from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg) (see section 4.2). Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g. uveitis) is recommended when rifabutin is co-administered with voriconazole.
Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Omeprazole (40 mg once daily) increased voriconazole Cmax and AUCby 15 % and 41 %, respectively. No dosage adjustment of voriconazole is recommended. Voriconazole increased omeprazole Cmax and AUCby 116 % and 280 %, respectively. When initiating voriconazole in patients already receiving omeprazole, it is recommended that the omeprazole dose be halved. The metabolism of other proton pump inhibitors which are CYP2C19 substrates may also be inhibited by voriconazole.
Oral Contraceptives Co-administration of voriconazole and an oral contraceptive (1 mg norethisterone and 0.035mg ethinylestradiol; once daily) in healthy female subjects resulted in increases in the Cmax and AUC of ethinylestradiol (36 % and 61 % respectively) and norethisterone (15 % and 53 % respectively). Voriconazole Cmax and AUC increased by 14 % and 46 % respectively. It is expected that the voriconazole levels will return to standard levels during the pill-free week. As the ratio between norethisterone and ethinylestradiol remained similar during interaction with voriconazole, their contraceptive activity would probably not be affected. Although no increase in the incidence of hormonal-related adverse events was observed in the clinical interaction study, higher estrogen and progestagen levels may cause notably nausea and menstrual disorders. Oral contraceptives containing doses other than 1mg norethisterone and 0.035 mg ethinylestradiol have not been studied.
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg every12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and AUC
Antiretroviral agents:
Indinavir (CYP3A4 inhibitor and substrate): Indinavir (800 mg three times daily) had no significant effect on voriconazole Cmax, Cmin and AUC. Voriconazole did not have a significant effect on Cmax and AUC of indinavir (800 mg three times daily).
Other HIV protease inhibitors (CYP3A4 inhibitors): In vitro studies suggest that voriconazole may inhibit the metabolism of HIV protease inhibitors (e.g. saquinavir, amprenavir and nelfinavir). In vitro studies also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors. However results of the combination of voriconazole with other HIV protease inhibitors cannot be predicted in humans only from in vitro studies. Patients should be carefully monitored for any occurrence of drug toxicity and/or loss of efficacy during the co- administration of voriconazole and HIV protease inhibitors.
Efavirenz (a non-nucleoside reverse transcriptase inhibitor) (CYP450 inducer; CYP3A4 inhibitor and substrate)): Standard doses of voriconazole and standard doses of efavirenz must not be co-administered. Steady-state efavirenz (400 mg orally once daily) decreased the steady state Cmax and AUC of voriconazole by an average of 61 % and 77 %, respectively, in healthy subjects. In the same study voriconazole at steady state increased the steady state Cmax and AUC of efavirenz by an average of 38 % and 44 % respectively, in healthy subjects.
In a separate study in healthy subjects, voriconazole dose of 300mg BID in combination with low dose efavirenz (300 mg once daily) did not lead to sufficient voriconazole exposure.
Following co-administration of voriconazole 400 mg twice daily with efavirenz 300 mg orally once daily, in healthy subjects, the AUC of voriconazole was decreased by 7 % and Cmax was increased by 23 %, compared to voriconazole 200 mg twice daily alone. (The AUC of efavirenz was increased by 17 % and Cmax was equivalent compared to efavirenz 600 mg once daily alone). These differerences were not considered to be clinically significant.
When voriconazole is co-administered with efavirenz, voriconazole maintenance dose should be increased to 400 mg twice daily and the efavirenz dose should be reduced by 50 %, i.e. to 300 mg once daily (see section 4.2). When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Non-nucleoside reverse transcriptase inhibitors (NNRTI) (CYP3A4 substrates, inhibitors or CYP450 inducers): In vitro studies show that the metabolism of voriconazole may be inhibited by delavirdine. Although not studied, the metabolism of voriconazole may be induced by nevirapine. An in-vivo study showed that voriconazole inhibited the metabolism of efavirenz. Voriconazole may also inhibit the metabolism of NNRTIs besides efavirenz. Patients should be carefully monitored for any occurrence of drug toxicity and/or lack of efficacy during the co-administration of voriconazole and NNRTIs. Dose adjustments are required when voriconazole is co-administered with efavirenz (see sections 4.2 and 4.4).
Pregnancy
No adequate information on the use of VFEND in pregnant women is available.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk forhumans is unknown.
VFEND must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.
Women of child-bearing potential
Women of child-bearing potential must always use effective contraception during treatment.
Lactation
The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with VFEND.
VFEND may have a moderate influence on the ability to drive and use machines. It may cause transient and reversible changes to vision, including blurring, altered/enhanced visual perception and/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operating machinery while experiencing these symptoms.
The safety profile of voriconazole is based on an integrated safety database of more than 2000 subjects (1655 patients in therapeutic trials). This represents a heterogeneous population, containing patients with haematological malignancy, HIV infected patients with oesophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidaemia or aspergillosis and healthy volunteers. Five hundred and sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over 6 months.
In the table below, since the majority of the studies were of an open nature all causality adverse events, by system organ c
Ceftazidim Hexal may be available in the countries listed below.
Ceftazidime is reported as an ingredient of Ceftazidim Hexal in the following countries:
Ceftazidime pentahydrate (a derivative of Ceftazidime) is reported as an ingredient of Ceftazidim Hexal in the following countries:
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Ciclonal may be available in the countries listed below.
Doxycycline hyclate (a derivative of Doxycycline) is reported as an ingredient of Ciclonal in the following countries:
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Cefthan may be available in the countries listed below.
Cefroxadine is reported as an ingredient of Cefthan in the following countries:
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Retrovir AZT may be available in the countries listed below.
Zidovudine is reported as an ingredient of Retrovir AZT in the following countries:
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Canipil may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Megestrol 17α-acetate (a derivative of Megestrol) is reported as an ingredient of Canipil in the following countries:
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Apo-Norflox may be available in the countries listed below.
Norfloxacin is reported as an ingredient of Apo-Norflox in the following countries:
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Hydrocortisone is reported as an ingredient of Massengill Towelette in the following countries:
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Famotidina Merck may be available in the countries listed below.
Famotidine is reported as an ingredient of Famotidina Merck in the following countries:
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Cidoten-V may be available in the countries listed below.
Betamethasone 17α-valerate (a derivative of Betamethasone) is reported as an ingredient of Cidoten-V in the following countries:
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Adco-Ethyl Chloride may be available in the countries listed below.
Ethyl Chloride is reported as an ingredient of Adco-Ethyl Chloride in the following countries:
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Preventing kidney stones. It is also used to increase the effectiveness of certain antibacterial medicines (methenamine mandelate and methenamine hippurate). It may also be used for other conditions as determined by your doctor.
K-Phos Original is a urinary acidifier. It works by increasing the amount of acid in the urine, which lowers the pH of the urine. This may reduce the growth of some bacteria in the urine and help dissolve calcium kidney stones.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with K-Phos Original. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with K-Phos Original. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if K-Phos Original may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use K-Phos Original as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use K-Phos Original.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Diarrhea; nausea; stomach pain; vomiting.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bone or joint pain; confusion; decreased urination; dizziness; irregular heartbeat; muscle cramps; numbness, tingling, pain, or weakness in the hands or feet; numbness or tingling around the lips; seizures; severe or persistent diarrhea; shortness of breath; unusual tiredness; unusual weakness or heaviness of the legs.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Store K-Phos Original at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep K-Phos Original out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about K-Phos Original. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Marxide may be available in the countries listed below.
Budesonide is reported as an ingredient of Marxide in the following countries:
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Ciprobay Uro may be available in the countries listed below.
Ciprofloxacin is reported as an ingredient of Ciprobay Uro in the following countries:
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Clarimed may be available in the countries listed below.
Clarithromycin is reported as an ingredient of Clarimed in the following countries:
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Ophaguttal may be available in the countries listed below.
Naphazoline hydrochloride (a derivative of Naphazoline) is reported as an ingredient of Ophaguttal in the following countries:
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Ciclopirox Olamina Biogalenica may be available in the countries listed below.
Ciclopirox olamine (a derivative of Ciclopirox) is reported as an ingredient of Ciclopirox Olamina Biogalenica in the following countries:
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Cusimolol may be available in the countries listed below.
Timolol maleate (a derivative of Timolol) is reported as an ingredient of Cusimolol in the following countries:
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Class: Antituberculosis Agents
VA Class: AM500
CAS Number: 1070-11-7
Brands: Myambutol
Antituberculosis agent.103 106 a
Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents.103 c d e
First-line agent for treatment of pulmonary TB; used in the initial intensive treatment phase.106
First-line agent for management of drug-resistant pulmonary TB.106
For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months).106 109 Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months,106 109 ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy.106 A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.106 109
Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.106
Treatment of M. avium complex (MAC) infections† in conjunction with other antimycobacterials, including infections in HIV-infected adults, adolescents, or children†.107 c d
For initial treatment of nodular/bronchiectatic pulmonary disease caused by macrolide-susceptible MAC, ATS and IDSA recommend a 3-times weekly regimen of clarithromycin (or azithromycin), ethambutol, and rifampin in most patients.107 For initial treatment of fibrocavitary or severe nodular/bronchiectatic pulmonary disease caused by macrolide-susceptible MAC, ATS and IDSA recommend a daily regimen of clarithromycin (or azithromycin), ethambutol, and rifampin (or rifabutin) and state that consideration can be given to adding amikacin or streptomycin during the first 2–3 months of treatment for extensive (especially fibrocavitary) disease or when previous therapy has failed.107 Although a 2-drug regimen of clarithromycin (or azithromycin) and ethambutol may be adequate for treatment of nodular/bronchiectatic MAC disease in some patients, such regimens should not be used for fibrocavitary disease because of the risk of emergence of macrolide resistance.107
For treatment of disseminated MAC disease, including in HIV-infected individuals, ATS, CDC, NIH, and IDSA recommend a regimen of clarithromycin (or azithromycin) and ethambutol with or without rifabutin.107 c d
Treatment of MAC infections is complicated and should be directed by clinicians familiar with mycobacterial diseases; consultation with a specialist is particularly important when the patient cannot tolerate first-line drugs or when the infection has not responded to prior therapy or is caused by macrolide-resistant MAC.107
Prevention of recurrence (secondary prophylaxis) of disseminated MAC infections† in HIV-infected adults, adolescents, and children†.108 c d USPHS/IDSA, CDC, NIH, IDSA, and others recommend clarithromycin (or azithromycin) given with ethambutol (with or without rifabutin) for secondary prophylaxis after the initial infection has been treated.108 c
Not used for primary prevention (primary prophylaxis) of disseminated MAC infection in HIV-infected individuals.108 Drug of choice for primary prophylaxis is azithromycin or clarithromycin;107 108 rifabutin (with or without azithromycin) is an alternative.107 108
Treatment of M. kansasii† infections in conjunction with other antimycobacterials.107 g ATS and IDSA recommend a regimen of isoniazid, rifampin, and ethambutol for treatment of pulmonary or disseminated infections caused by rifampin-susceptible M. kansasii.107 If rifampin-resistant M. kansasii are involved, ATS and IDSA recommend a 3-drug regimen based on results of in vitro susceptibility, including clarithromycin (or azithromycin), moxifloxacin, ethambutol, sulfamethoxazole, or streptomycin.107
Treatment of M. marinum† infections in conjunction with other antimycobacterials (e.g., clarithromycin and/or rifampin).107 i j l Optimum regimens not identified.107 i j l Monotherapy (minocycline, clarithromycin, doxycycline, co-trimoxazole) may be effective for superficial cutaneous infections,j but a multiple-drug regimen usually used for severe cutaneous infections or infections in immunocompromised individuals.i j
Treatment of M. xenopi† infections in conjunction with other antimycobacterials.107 Optimum regimens not established; in vivo response may not correlate with in vitro susceptibility.107 ATS and IDSA state that a regimen of clarithromycin, rifampin, and ethambutol generally has been used, although rate of relapse is high.107 A regimen of isoniazid, rifampin (or rifabutin), ethambutol, and clarithromycin (with or without streptomycin during initial treatment) also has been suggested.107
Administer orally without regard to meals.103 e
Available as ethambutol hydrochloride; dosage expressed in terms of the salt.103 e
Must be used in conjunction with other antimycobacterial agents for treatment of active (clinical) TB,103 108 e treatment or prevention of MAC infections†,107 108 c or treatment of other mycobacterial infections†.107
Can be used in daily or intermittent (e.g., 2 or 3 times weekly) multiple-drug TB regimens.106 109 c d
Children <15 years of age or weighing ≤40 kg†: 15–25 mg/kg once daily recommended by ATS, CDC, IDSA, AAP, and others.106 109 d h If an intermittent regimen is used, 50 mg/kg twice weekly.106 109 d h ATS, CDC, and IDSA recommend that children receive a maximum of 1 g per dose;106 d AAP and others recommend a maximum of 2.5 g per dose.109 h
Adolescents ≥15 years of age weighing 40–55 kg: 800 mg daily, 2 g twice weekly, or 1.2 g 3 times weekly recommended by ATS, CDC, and IDSA.106
Adolescents ≥15 years of age weighing 56–75 kg: 1.2 g daily, 2.8 g twice weekly, or 2 g 3 times weekly recommended by ATS, CDC, and IDSA.106
Adolescents ≥15 years of age weighing 76-90 kg: 1.6 g daily, 4 g twice weekly, or 2.4 g 3 times weekly recommended by ATS, CDC, and IDSA.106
Adolescents: AAP and others recommend 15–25 mg/kg (up to 2.5 g) once daily or 50 mg/kg twice weekly (up to 2.5 g per dose).109 h
15–25 mg/kg (up to 1 g) once daily.d h Used in conjunction with clarithromycin (7.5–15 mg/kg [up to 500 mg] twice daily) or azithromycin (10–12 mg/kg [up to 500 mg] once daily) with or without rifabutin (10–20 mg/kg [up to 300 mg] once daily).d
15 mg/kg once daily in conjunction with either clarithromycin (500 mg twice daily) or azithromycin (500 mg once daily) with or without rifabutin (300 mg once daily).107 c
15 mg/kg (up to 900 mg) once daily.108 h Used in conjunction with clarithromycin (7.5 mg/kg [up to 500 mg] twice daily) or azithromycin (5 mg/kg [up to 250 mg] once daily) with or without rifabutin (5 mg/kg [up to 300 mg] once daily).108
Secondary prophylaxis to prevent MAC recurrence in HIV-infected children usually continued for life.108 The safety of discontinuing secondary MAC prophylaxis in children whose CD4+ T-cell count increases in response to antiretroviral therapy has not been studied.108
15 mg/kg (up to 900 mg) once daily.108 c h Used in conjunction with either clarithromycin (500 mg twice daily) or azithromycin (500 mg once daily) with or without rifabutin (300 mg once daily).108 c
Secondary prophylaxis to prevent MAC recurrence usually continued for life in HIV-infected adolescents.108 c
Consideration can be given to discontinuing such prophylaxis after ≥12 months in those who remain asymptomatic with respect to MAC and have an increase in CD4+ T-cell count to >100/mm3 that has been sustained for ≥6 months.108 c Reinitiate prophylaxis if CD4+ T-cell count decreases to <100/mm3.108 c
Manufacturers recommend 15 mg/kg once daily in previously untreated adults.103 e In previously treated adults, manufacturers recommend 25 mg/kg once daily for 60 days, followed by 15 mg/kg once daily.103 e
Adults weighing 40–55 kg: 800 mg once daily, 2 g twice weekly, or 1.2 g 3 times weekly recommended by ATS, CDC, and IDSA.106 c
Adults weighing 56–75 kg: 1.2 g once daily, 2.8 g twice weekly, or 2 g 3 times weekly recommended by ATS, CDC, and IDSA.106 c
Adults weighing 76-90 kg: 1.6 g once daily, 4 g twice weekly, or 2.4 g 3 times weekly recommended by ATS, CDC, and IDSA.106 c
25 mg/kg 3 times weekly in conjunction with rifampin (600 mg 3 times weekly) and either clarithromycin (1 g 3 times weekly) or azithromycin (500 mg 3 times weekly) recommended by ATS and IDSA.107 Continue until patient has been culture negative on treatment for 1 year.107
Intermittent (3-times weekly) regimen is not recommended for those with cavitary or moderate or severe disease or those who have been previously treated.107
15 mg/kg once daily in conjunction with either rifampin (10 mg/kg [up to 600 mg] once daily) or rifabutin (150–300 mg once daily) and either clarithromycin (0.5–1 g daily) or azithromycin (250 mg once daily) recommended by ATS and IDSA.107 Continue until patient has been culture negative on treatment for 1 year.107 Consideration can be given to including amikacin or streptomycin 3-times weekly during the first 2–3 months of treatment for extensive, especially fibrocavitary, disease or when previous therapy has failed.107
15 mg/kg once daily in conjunction with either clarithromycin (500 mg twice daily) or azithromycin (500 mg once daily) with or without rifabutin (300 mg once daily) recommended by ATS, CDC, and IDSA.107 c
15 mg/kg once daily.108 c Used in conjunction with either clarithromycin (500 mg twice daily) or azithromycin (500 mg once daily) with or without rifabutin (300 mg once daily).108 c
Secondary prophylaxis to prevent MAC recurrence usually continued for life in HIV-infected adults.108
Consideration can be given to discontinuing such prophylaxis after ≥12 months in those who remain asymptomatic with respect to MAC and have an increase in CD4+ T-cell count to >100/mm3 that has been sustained for ≥6 months.108 c Reinitiate prophylaxis if CD4+ T-cell count decreases to <100/mm3.108 c
15 mg/kg once daily in conjunction with rifampin (10 mg/kg [up to 600 mg] daily), isoniazid (5 mg/kg [up to 300 mg] daily), and pyridoxine (50 mg daily) recommended by ATS and IDSA.107
Continue until patient has been culture negative on treatment for 1 year.107 A longer duration may be needed in HIV-infected individuals with disseminated infections.107
15–25 mg/kg daily in conjunction with rifampin (600 mg daily) and/or clarithromycin.107 i j l
Optimal duration of treatment not known; continue for 3–6 months or until at least 1–2 months after resolution of symptoms.107 i j l
Maximum 1 g per dose recommended by ATS, CDC, and IDSA for once-daily or twice-weekly regimens;106 d maximum 2.5 g per dose recommended by AAP and others for once-daily or twice-weekly regimens.109 h
Maximum 1 g once daily for treatment of disseminated MAC infections.d Maximum 900 mg once daily for prevention of MAC recurrence (secondary prophylaxis).108
Reduce dosage based on degree of renal impairment and serum concentrations of the drug.103 106 c e h
Some experts recommend 15 mg/kg once every 24–36 hours in adults with Clcr 10–50 mL/minute, 15 mg/kg once every 48 hours in those with Clcr <10 mL/minute, and 15 mg/kg 3 times weekly (after hemodialysis) in those undergoing hemodialysis.c Others recommend 15–20 mg/kg 3 times weekly (after dialysis) in adults with end-state renal disease (Clcr <30 mL/minute, on hemodialysis).106
In children with renal impairment, some experts recommend that the usual dose be given once every 24 hours in those with Clcr >50 mL/minute or once every 24–36 hours in those with Clcr 10–50 mL/minute.h In children with Clcr <10 mL/minute, these experts recommend that a decreased dose be given once every 48 hours.h Supplemental doses are recommended after hemodialysis.h
Known hypersensitivity to ethambutol or any ingredient in the formulation.103 e
Optic neuritis, unless clinical judgment deems it necessary to use the drug.103 e
Patients unable to appreciate and report visual adverse effects or changes in vision (e.g., young children, unconscious patients).103 (See Pediatric Use under Cautions.)
Decreased visual acuity, constriction of visual fields, central and peripheral scotomas, and loss of red-green color discrimination reported.103 106 a e May be due to optic neuritis, but has occurred in the absence of a diagnosis of optic or retrobulbar neuritis.103 e May be related to dose and duration of treatment.103 106 e
Perform ophthalmic evaluation (ophthalmoscopy, finger perimetry, test for color discrimination) at baseline and periodically during treatment.103 106 e Test each eye separately and together since change in visual acuity may be unilateral or bilateral.103 e Evaluate monthly in patients receiving >15 mg/kg daily, in those receiving the drug for >2 months, and in those with renal impairment.103 106 e
Use with caution in patients with ocular defects (e.g., cataracts, recurrent ocular inflammatory conditions, optic neuritis, diabetic retinopathy) that make visual changes difficult to detect or evaluate; weigh benefits versus possible visual deterioration in these patients.103 e
Discontinue if substantial changes in visual acuity occur.103 e Changes in visual acuity usually reversible (over several weeks or months), but irreversible blindness has been reported.103 e
Liver toxicities, including fatalities, have been reported.103
Perform baseline and periodic assessment of hepatic function.103 e
Anaphylactoid reactions, dermatitis, pruritus reported.103
Should not be used alone for the treatment of active TB; must be given in conjunction with other antituberculosis agents.106
Clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing should be obtained prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response.106 The antituberculosis regimen should be modified as needed.106 Patients with positive cultures after 4 months of treatment should be considered to have failed treatment (usually as the result of noncompliance or drug-resistant TB).106
Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical.106 Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.106
To ensure compliance, ATS, CDC, IDSA, and AAP recommend that directly observed (supervised) therapy (DOT) be used for treatment of active (clinical) TB whenever possible, especially when intermittent regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant M. tuberculosis is involved.106 109 c d
Assess organ system function (e.g., renal, hepatic, hematopoietic) at baseline and periodically during treatment.103 e
Category C.103
Ophthalmic abnormalities have been reported in infants born to women who received antituberculosis regimens that included ethambutol during pregnancy.103
The ATS, CDC, IDSA, AAP and others consider ethambutol safe for use in pregnant women;106 108 109 AAP states potential benefits outweigh the risks to the infant.109
Distributed into milk; use only if possible benefits outweigh potential risks.103
AAP considers ethambutol compatible with breast-feeding.b
Safety not established in children <13 years of age; manufacturers do not recommend use in this age group.103 e Has been used in pediatric patients without unusual adverse effects.d
ATS, CDC, IDSA, and AAP state that ethambutol can be used safety in older children, but should be used with caution in children in whom it may be difficult to monitor visual acuity (e.g., <5 years of age).106 109 If used in pediatric patients, perform ophthalmic evaluations once monthly during treatment.d
No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity in this age group cannot be ruled out.103
ATS, CDC, and IDSA state that ethambutol can be used safely in patients with hepatic disease.106
Use with caution; dosage reduction based on serum concentrations is advised.103 e Closely monitor visual acuity and color discrimination (i.e., monthly).103 106 (See Renal Impairment under Dosage and Administration.)
Ophthalmic effects (decreased visual acuity, scotoma, color blindness, visual defect), joint pain, GI effects (anorexia, nausea, vomiting, GI upset, abdominal pain), fever, malaise, headache, dizziness, mental confusion.103 e
Drug | Interaction | Comments |
|---|---|---|
Antacids | Aluminum-containing antacids: Decreased ethambutol serum concentrations and urinary excretion; possible decreased oral absorption of the antimycobacterial103 | Administer aluminum-containing antacids ≥4 hours after ethambutol103 |
Rifabutin | Pharmacokinetic interaction unlikelyf |
75–80% of an oral dose is absorbed from the GI tract;a peak plasma concentrations achieved within 2–4 hours.103 e
Food does not appear to affect absorption.103 e
Serum concentrations are higher in patients with renal impairment.a
Widely distributed into most body tissues and fluids.a Highest concentrations are found in erythrocytes, kidneys, lungs, and saliva; lower drug concentrations are found in ascitic fluid, pleural fluid, brain, and CSF.a
Crosses the placenta and is distributed into cord blood and amniotic fluid.100
Distributed into milk.103
8–22%.a
Undergoes oxidation in the liver to an aldehyde intermediate which is converted to a dicarboxylic acid derivative.103 e
Excreted in urine as unchanged drug (50%) and metabolites (8–15%) and in feces as unchanged drug (20–22%).103 e
Removed by peritoneal dialysis and to a lesser extent by hemodialysis.a
3.3 hours.a
Half-life prolonged in patients with impaired renal or hepatic function.a Half-life may be ≥7 hours in patients with renal failure.a
15–30°Ce or 20–25°C103 , depending on the manufacturer. Protect from light and moisture.e
Bacteriostatic in action.a
Appears to inhibit the synthesis of one or more metabolites in susceptible bacteria resulting in impairment of cellular metabolism, arrest of multiplication, and cell death.103 e
A highly specific agent; active only against Mycobacterium.103 a Active against M. tuberculosis,a M. avium complex (MAC),a M. bovis,a M. kansasii,107 a g and some strains of M. fortuitum.a Although M. marinum may be susceptible,107 a resistance has been reported.k Active in vitro against M. gordonae,107 M. malmoense,107 and M. smegmatis.107 Has limited activity against M. genavense.107 M. haemophilum107 and some strains of M. xenopi are resistant.107
Natural and acquired resistance to ethambutol demonstrated in vitro and in vivo in strains of M. tuberculosis.103 a
No evidence of cross-resistance with other currently available antimycobacterials.103 e
Advise patients that poor compliance with antituberculosis regimens can result in treatment failure and development of drug-resistant TB, which can be life-threatening and lead to other serious health risks.106
Importance of completing full course of therapy; importance of not missing any doses.103
Importance of promptly informing clinicians of any change in visual acuity.103 e
Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.103
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.103
Importance of informing patients of other important precautionary information.103 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 100 mg | Ethambutol Tablets | VersaPharm |
Myambutol | X-Gen | |||
400 mg | Ethambutol Tablets | Barr, VersaPharm | ||
Myambutol (scored) | X-Gen |
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Ethambutol HCl 400MG Tablets (VERSAPHARM): 30/$55.99 or 90/$153.98
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
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