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Overview
What is Vantas?
VANTAS (histrelin acetate) implant is a sterile, non-biodegradable, diffusion-controlled hydrogel polymer reservoir containing histrelin acetate, a synthetic nonapeptide analog of the naturally occurring gonadotropin releasing hormone (GnRH). VANTAS is designed to deliver approximately 50 mcg histrelin acetate per day (equivalent to approximately 41 mcg histrelin per day) over 12 months.
The sterile VANTAS implant looks like a small thin flexible tube and consists of a 50-mg histrelin acetate drug core inside a 3.5 cm by 3 mm, cylindrical hydrogel polymer reservoir (Figure A). The implant may appear partially to completely full with variation in color from off-white to light brown. The color may be uneven within the core.
Figure A. VANTAS Implant diagram (not to scale)
Histrelin acetate is chemically described as: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-Ntbenzyl-D-histidyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) [CHNO (1.7-2.8 moles) CHCOOH, (0.6-7.0 moles) HO], with the molecular weight of 1443.70 (or 1323.50 as histrelin base).
Histrelin acetate has the following structural formula:
The drug core also contains the inactive ingredient stearic acid NF. The hydrogel polymer reservoir is a hydrophilic cartridge composed of 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, trimethylolpropane trimethacrylate, benzoin methyl ether, Perkadox-16, and Triton X-100. Each implant is packaged hydrated in a glass vial containing 2 mL of sterile 1.8% sodium chloride solution. The implant is primed for immediate release of the drug upon insertion.
A single use, sterile Insertion Tool is provided along with the implant that may be used for the placement of the implant into the subcutaneous tissue of the inner aspect of the upper arm. The Insertion Tool is enclosed in a sterile bag and is provided separately from the implant in the Implantation Kit .
What does Vantas look like?
What are the available doses of Vantas?
Subcutaneous implant: 50 mg histrelin acetate ().
What should I talk to my health care provider before I take Vantas?
How should I use Vantas?
VANTAS is indicated for the palliative treatment of advanced prostate cancer.
The recommended dose of VANTAS is one implant for 12 months. Each implant contains 50 mg histrelin acetate to deliver 41 mg histrelin. The implant is inserted subcutaneously in the inner aspect of the upper arm and provides continuous release of histrelin (50 mcg/day) for 12 months of hormonal therapy. VANTAS should be removed after 12 months of therapy (the implant has been designed to allow for a few additional weeks of histrelin release, in order to allow flexibility of medical appointments). At the time an implant is removed, another implant may be inserted to continue therapy.
What interacts with Vantas?
Sorry No Records found
What are the warnings of Vantas?
Sorry No Records found
What are the precautions of Vantas?
Sorry No Records found
What are the side effects of Vantas?
Sorry No records found
What should I look out for while using Vantas?
Known hypersensitivity to GnRH or GnRH analogs ().
Pregnancy: VANTAS can cause fetal harm when used during pregnancy ().
What might happen if I take too much Vantas?
Histrelin acetate injection of up to 200 mcg/kg (rats, rabbits), or 2000 mcg/kg (mice) resulted in no systemic toxicity. This represents 20 to 200 times the maximal recommended human dose of 10 mcg/kg/day. Adverse event profiles were similar in patients receiving one, two or four VANTAS implants.
How should I store and handle Vantas?
Storage:VANTAS (NDC 67979-500-01) is supplied in a carton containing 2 inner cartons, one for the VANTAS implant and one for the VANTAS Implantation Kit: The VANTAS implant contains 50 mg of histrelin acetate. The VANTAS implant carton contains a cold pack for refrigerated shipment and a small carton containing an amber plastic pouch. Inside the pouch is a glass vial with a Teflon-coated stopper and an aluminum seal, containing the implant in 2 mL of sterile 1.8% sodium chloride solution. (: The 3.5 mL vial is not completely filled with saline.) Upon receipt, refrigerate the small carton containing the amber plastic pouch and glass vial (with the implant inside) until the day of insertion. The implant vial should not be opened until just before the time of insertionStore the implant refrigerated, 2-8°C (36-46°F), in the unopened glass vial with the sterile 1.8% sodium chloride solution, overwrapped in the amber plastic pouch and carton, until the expiration date provided. Excursion permitted to 25°C (77°F) for 7 days. Protect from light. Do not freeze.Store the VANTAS Implantation Kit at room temperature only.The VANTAS Implantation Kit carton contains one each of the following (individually wrapped in sterile packaging): implant insertion tool, #15 disposable scalpel, syringe with 18 gauge needle, 25 gauge 1.5” needle, SS mosquito clamp, benzoin tincture antiseptic, alcohol swabs (2 packages), fenestrated drape, non-fenestrated drape, skin antiseptic swab, gauze sponges, surgical closure strips, coated absorbable sutures, cohesive bandage, and a local anesthetic (e.g., lidocaine HCl 1% with epinephrine or lidocaine HCl 1%).VANTAS (NDC 67979-500-01) is supplied in a carton containing 2 inner cartons, one for the VANTAS implant and one for the VANTAS Implantation Kit: The VANTAS implant contains 50 mg of histrelin acetate. The VANTAS implant carton contains a cold pack for refrigerated shipment and a small carton containing an amber plastic pouch. Inside the pouch is a glass vial with a Teflon-coated stopper and an aluminum seal, containing the implant in 2 mL of sterile 1.8% sodium chloride solution. (: The 3.5 mL vial is not completely filled with saline.) Upon receipt, refrigerate the small carton containing the amber plastic pouch and glass vial (with the implant inside) until the day of insertion. The implant vial should not be opened until just before the time of insertionStore the implant refrigerated, 2-8°C (36-46°F), in the unopened glass vial with the sterile 1.8% sodium chloride solution, overwrapped in the amber plastic pouch and carton, until the expiration date provided. Excursion permitted to 25°C (77°F) for 7 days. Protect from light. Do not freeze.Store the VANTAS Implantation Kit at room temperature only.The VANTAS Implantation Kit carton contains one each of the following (individually wrapped in sterile packaging): implant insertion tool, #15 disposable scalpel, syringe with 18 gauge needle, 25 gauge 1.5” needle, SS mosquito clamp, benzoin tincture antiseptic, alcohol swabs (2 packages), fenestrated drape, non-fenestrated drape, skin antiseptic swab, gauze sponges, surgical closure strips, coated absorbable sutures, cohesive bandage, and a local anesthetic (e.g., lidocaine HCl 1% with epinephrine or lidocaine HCl 1%).VANTAS (NDC 67979-500-01) is supplied in a carton containing 2 inner cartons, one for the VANTAS implant and one for the VANTAS Implantation Kit: The VANTAS implant contains 50 mg of histrelin acetate. The VANTAS implant carton contains a cold pack for refrigerated shipment and a small carton containing an amber plastic pouch. Inside the pouch is a glass vial with a Teflon-coated stopper and an aluminum seal, containing the implant in 2 mL of sterile 1.8% sodium chloride solution. (: The 3.5 mL vial is not completely filled with saline.) Upon receipt, refrigerate the small carton containing the amber plastic pouch and glass vial (with the implant inside) until the day of insertion. The implant vial should not be opened until just before the time of insertionStore the implant refrigerated, 2-8°C (36-46°F), in the unopened glass vial with the sterile 1.8% sodium chloride solution, overwrapped in the amber plastic pouch and carton, until the expiration date provided. Excursion permitted to 25°C (77°F) for 7 days. Protect from light. Do not freeze.Store the VANTAS Implantation Kit at room temperature only.The VANTAS Implantation Kit carton contains one each of the following (individually wrapped in sterile packaging): implant insertion tool, #15 disposable scalpel, syringe with 18 gauge needle, 25 gauge 1.5” needle, SS mosquito clamp, benzoin tincture antiseptic, alcohol swabs (2 packages), fenestrated drape, non-fenestrated drape, skin antiseptic swab, gauze sponges, surgical closure strips, coated absorbable sutures, cohesive bandage, and a local anesthetic (e.g., lidocaine HCl 1% with epinephrine or lidocaine HCl 1%).VANTAS (NDC 67979-500-01) is supplied in a carton containing 2 inner cartons, one for the VANTAS implant and one for the VANTAS Implantation Kit: The VANTAS implant contains 50 mg of histrelin acetate. The VANTAS implant carton contains a cold pack for refrigerated shipment and a small carton containing an amber plastic pouch. Inside the pouch is a glass vial with a Teflon-coated stopper and an aluminum seal, containing the implant in 2 mL of sterile 1.8% sodium chloride solution. (: The 3.5 mL vial is not completely filled with saline.) Upon receipt, refrigerate the small carton containing the amber plastic pouch and glass vial (with the implant inside) until the day of insertion. The implant vial should not be opened until just before the time of insertionStore the implant refrigerated, 2-8°C (36-46°F), in the unopened glass vial with the sterile 1.8% sodium chloride solution, overwrapped in the amber plastic pouch and carton, until the expiration date provided. Excursion permitted to 25°C (77°F) for 7 days. Protect from light. Do not freeze.Store the VANTAS Implantation Kit at room temperature only.The VANTAS Implantation Kit carton contains one each of the following (individually wrapped in sterile packaging): implant insertion tool, #15 disposable scalpel, syringe with 18 gauge needle, 25 gauge 1.5” needle, SS mosquito clamp, benzoin tincture antiseptic, alcohol swabs (2 packages), fenestrated drape, non-fenestrated drape, skin antiseptic swab, gauze sponges, surgical closure strips, coated absorbable sutures, cohesive bandage, and a local anesthetic (e.g., lidocaine HCl 1% with epinephrine or lidocaine HCl 1%).VANTAS (NDC 67979-500-01) is supplied in a carton containing 2 inner cartons, one for the VANTAS implant and one for the VANTAS Implantation Kit: The VANTAS implant contains 50 mg of histrelin acetate. The VANTAS implant carton contains a cold pack for refrigerated shipment and a small carton containing an amber plastic pouch. Inside the pouch is a glass vial with a Teflon-coated stopper and an aluminum seal, containing the implant in 2 mL of sterile 1.8% sodium chloride solution. (: The 3.5 mL vial is not completely filled with saline.) Upon receipt, refrigerate the small carton containing the amber plastic pouch and glass vial (with the implant inside) until the day of insertion. The implant vial should not be opened until just before the time of insertionStore the implant refrigerated, 2-8°C (36-46°F), in the unopened glass vial with the sterile 1.8% sodium chloride solution, overwrapped in the amber plastic pouch and carton, until the expiration date provided. Excursion permitted to 25°C (77°F) for 7 days. Protect from light. Do not freeze.Store the VANTAS Implantation Kit at room temperature only.The VANTAS Implantation Kit carton contains one each of the following (individually wrapped in sterile packaging): implant insertion tool, #15 disposable scalpel, syringe with 18 gauge needle, 25 gauge 1.5” needle, SS mosquito clamp, benzoin tincture antiseptic, alcohol swabs (2 packages), fenestrated drape, non-fenestrated drape, skin antiseptic swab, gauze sponges, surgical closure strips, coated absorbable sutures, cohesive bandage, and a local anesthetic (e.g., lidocaine HCl 1% with epinephrine or lidocaine HCl 1%).VANTAS (NDC 67979-500-01) is supplied in a carton containing 2 inner cartons, one for the VANTAS implant and one for the VANTAS Implantation Kit: The VANTAS implant contains 50 mg of histrelin acetate. The VANTAS implant carton contains a cold pack for refrigerated shipment and a small carton containing an amber plastic pouch. Inside the pouch is a glass vial with a Teflon-coated stopper and an aluminum seal, containing the implant in 2 mL of sterile 1.8% sodium chloride solution. (: The 3.5 mL vial is not completely filled with saline.) Upon receipt, refrigerate the small carton containing the amber plastic pouch and glass vial (with the implant inside) until the day of insertion. The implant vial should not be opened until just before the time of insertionStore the implant refrigerated, 2-8°C (36-46°F), in the unopened glass vial with the sterile 1.8% sodium chloride solution, overwrapped in the amber plastic pouch and carton, until the expiration date provided. Excursion permitted to 25°C (77°F) for 7 days. Protect from light. Do not freeze.Store the VANTAS Implantation Kit at room temperature only.The VANTAS Implantation Kit carton contains one each of the following (individually wrapped in sterile packaging): implant insertion tool, #15 disposable scalpel, syringe with 18 gauge needle, 25 gauge 1.5” needle, SS mosquito clamp, benzoin tincture antiseptic, alcohol swabs (2 packages), fenestrated drape, non-fenestrated drape, skin antiseptic swab, gauze sponges, surgical closure strips, coated absorbable sutures, cohesive bandage, and a local anesthetic (e.g., lidocaine HCl 1% with epinephrine or lidocaine HCl 1%).
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Clinical Information
Chemical Structure
No Image found
Clinical Pharmacology
Histrelin acetate is a gonadotropin releasing hormone (GnRH) agonist that acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Both animal and human studies indicate that following an initial stimulatory phase, chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin which, in turn, causes a reduction in testicular steroidogenesis.
In humans, administration of histrelin acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males); however, continuous administration of histrelin acetate results in decreased levels of LH and FSH due to a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. In males, testosterone is reduced to castration levels. These decreases occur within 2 to 4 weeks after initiation of treatment.
Histrelin acetate is not active when given orally.
Non-Clinical Toxicology
Known hypersensitivity to GnRH or GnRH analogs ().
Pregnancy: VANTAS can cause fetal harm when used during pregnancy ().
(See
and
.) Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 2C19, and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 coadministered with fluconazole. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between Fluconazole and the following agents/classes have been observed. These are described in greater detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Voriconazole
Tacrolimus
Short-acting benzodiazepines
Tofacitinib
Triazolam
Oral Contraceptives
Pimozide
Quinidine
Hydrochlorothiazide
Alfentanil
Amitriptyline, nortriptyline
Amphotericin B
Azithromycin
Carbamazepine
Calcium Channel Blockers
Celecoxib
Cyclophosphamide
Fentanyl
Halofantrine
HMG-CoA reductase inhibitors
Losartan
Methadone
Non-steroidal anti-inflammatory drugs
Prednisone
Saquinavir
Sirolimus
Vinca
Alkaloids
Vitamin A
Zidovudine
Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of fluconazole with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined fluconazole and glyburide use. Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When fluconazole is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See
)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See
.)
Phenytoin: Fluconazole increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving fluconazole and phenytoin is recommended. (See
)
Cyclosporine: Fluconazole significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving fluconazole and cyclosporine. (See
.) This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration.
Rifampin: Rifampin enhances the metabolism of concurrently administered fluconazole. Depending on clinical circumstances, consideration should be given to increasing the dose of fluconazole when it is administered with rifampin. (See
)
Theophylline: Fluconazole increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving fluconazole and theophylline is recommended. (See
.)
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See
and
) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored.
Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval.The combined use of fluconazole with cisapride is contraindicated. (See
)
Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.
Rifabutin: There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See
.)
Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See
)
Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. (See
.)
Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See
.)
Tofacitinib: Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole, a combined moderate CYP3A4 and potent CYP2C19 inhibitor. Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the XELJANZ
[tofacitinib] label). (See
.)
Triazolam: Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C
by 20 to 32%, and increases t½ by 25 to 50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.
Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Pimozide: Although not studied
or
, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.
Quinidine: Although not studied
or
, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See
.
Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics.
Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T
of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.
Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with
, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.
Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.
Calcium Channel Blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine). Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.
Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib C
and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.
Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.
HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs: The C
and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.
Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.
Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.
Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases clearance of saquinavir by approximately 50% due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.
Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.
Vitamin A: Based on a case report in one patient receiving combination therapy with all-transretinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.
Zidovudine: Fluconazole increases C
and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.
Physicians should be aware that interaction studies with medications other than those listed in the
section have not been conducted, but such interactions may occur.
VANTAS causes a transient increase in serum concentrations of testosterone during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or ureteral or bladder outlet obstruction.
