Isavuconazole; Uses, Dosage, Side Effects, Interactions, Pragnancy

Isavuconazole; Uses, Dosage, Side Effects, Interactions, Pragnancy

Isavuconazole is a water-soluble triazole prodrug with broad-spectrum antifungal activity. Isavuconazole is absorbed easily, given either orally or intravenously, and is hydrolyzed to its active moiety BAL4815 by plasma esterases. BAL4815 inhibits fungal cytochrome P450 lanosterol 14-alpha-demethylase (CYP51) that catalyzes the conversion of lanosterol to ergosterol, an important component of the fungal cell membrane. Enzyme inhibition by this agent leads to a decrease in ergosterol pool and therefore disturbs synthesis of the fungal cell membrane, thereby increasing cell membrane permeability and promoting loss of essential intracellular elements. This ultimately causes fungal cell lysis and death.

 

Isavuconazole sulfate is a prodrug for isavuconazole which is a triazole antifungal agent. Isavuconazole is used to treat invasive aspergillosis and invasive mucormycosis. Isavuconazole displays antifungal activity (both in vitro and in clinical infections) against most strains of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Rizopus oryzae, and Mucormycetes species. Unlike other azole antifungals, isavuconazonium is NOT indicated for the treatment of infections caused by other fungal species, such as Candida, Blastomyces, nor Histoplasma.

Mechanism of Action of Isavuconazole

Like other azole antifungals, isavuconazole (the active metabolite of isavuconazonium) exerts its antifungal activity by inhibiting the synthesis of ergosterol, an essential component of fungal cell membrane. Azole antifungals block ergosterol synthesis by inhibiting 14-alpha-demethylase, a cytochrome P-450 dependent enzyme, which is needed to convert lanosterol to ergosterol. The depletion of ergosterol within the fungal cell membrane results in increased cellular permeability causing leakage of cellular contents. Isavuconazole displays antifungal activity (both in vitro and in clinical infections) against most strains of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Rizopus oryzae, and Mucormycetes species. Unlike other azole antifungals, isavuconazonium is NOT indicated for the treatment of infections caused by other fungal species, such as Candida, Blastomyces, nor Histoplasma. Cross-resistance with other azole antifungals may be possible due to common modes of action. Potential resistance mechanisms include substitutions in the target gene CYP51, changes in sterol profile, and increased efflux pump activity.

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Isavuconazole displays fungicidal actions by disrupting the biosynthesis of ergosterol, which is a key component of the fungal cell membrane. It inhibits cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase that mediates the conversion of lanosterol to ergosterol. The side arm of the active isavuconazole molecule allows for greater affinity for the binding pocket in the fungal CYP51 protein by orienting the triazole ring of the molecule to engage with the heme moiety at the bottom of the binding pocket. This explains the wide antifungal spectrum of isavuconazole and possible cross-resistance to other triazoles. As a result of lanosterol 14-alpha-demethylase inhibition, toxic methylated sterol precursors such as 14-α-methylated lanosterol, 4,14-dimethyl-zymosterol, and 24-methylene dihydro lanosterol alter the function of fungal membrane and accumulate within the fungal cytoplasm [A32029]. Depletion of ergosterol within the fungal cell membrane leads to decreased structural integrity and function of the cell membrane, inhibited fungal cell growth and replication [A32026], and ultimately cell death. Mammalian cell demethylation is less sensitive to isavuconazole inhibition [FDA Label]. Mechanism of resistance and reduced susceptibility to isavuconazole arises from mutations in the fungal cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase [L1482]. Other multiple mechanisms leading to resistance, including changes in sterol profile and elevated efflux pump activity of fungal species, cannot be excluded

Indications of Isavuconazole

  • invasive aspergillosis
  • mucormycosis in patients for whom amphotericin B is inappropriate
  • Patients with candidemia or with an invasive Candida infection
  • Presence of fever, hypothermia or other appropriate local sign of infection
  • Female patients must be non-lactating and at no risk of pregnancy
  • Patients with a sole diagnosis of mucocutaneous candidiasis, i.e. oropharyngeal, esophageal or genital candidiasis; or candidal lower urinary tract infection or Candida isolated solely from respiratory tract specimens
  • Patients with candidemia who failed a previous antifungal therapy for the same infection
  • Patients previously enrolled in a phase III study with isavuconazole
  • Patients with a body weight <40kg
  • Indicated for patients 18 years of age and older for the treatment of invasive aspergillosis [FDA Label].
  • Indicated for patients 18 years of age and older for the treatment of invasive mucormycosis [FDA Label], including patients where treatment amphotericin B is inappropriate

Contra-Indications of Isavuconazole

Isavuconazole should not be given to anyone with a history of allergic reaction to it, nor to anyone taking ketoconazole or high-dose ritonavir. It should not be given to anyone with a family history of short QT syndrome. It has not been tested in children.

In preclinical studies, isavuconazole caused birth defects; it has not been tested in pregnant women. Women who are pregnant should not take it and women taking it should not get pregnant. It is excreted in breast milk so people should not breast-feed while taking it.

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Dosages of Isavuconazole

Treatment of invasive aspergillosis and invasive mucormycosis

  • Initiate treatment with a loading dose of 2 capsules (372 mg) PO every 8 hours for 6 doses. Then, beginning 12 to 24 hours after the last loading dose, administer a maintenance dose of 2 capsules (372 mg) PO once daily.
  • There is an established bioequivalence with the IV formulation; an additional loading dose is NOT required when switching the patient to PO dosing.
  • The Infectious Diseases Society of America (IDSA) recommends the use of isavuconazole as an alternative therapy for the treatment of invasive aspergillosis.
  • The doses recommended by the IDSA (i.e., 200 mg every 8 hours for 6 doses, followed by 200 mg daily) are expressed as isavuconazole equivalents for isavuconazonium sulfate.

Treatment of esophageal candidiasis

  • 372 mg PO once then 93 mg PO daily or 744 mg PO once then 186 mg PO daily or 744 mg PO weekly for 14 to 21 days.

Oral dosage

  • Dosage not established. 800 mg, 800 mg, 400 mg PO loading doses given at equal intervals on day 1 then 400 mg PO twice daily on day 2 then 400 mg PO once daily.

Side Effects of Isavuconazole

The most common 

Common

Rare

Drug Interactions of Isavuconazole

Co-administered medicinal product by therapeutic area Effects on drug concentrations / Geometric Mean Change (%) in AUC, Cmax

(Mode of action)

Recommendation concerning co-administration
Anticonvulsants
Carbamazepine, phenobarbital, and phenytoin

(strong CYP3A4/5 inducers)

Isavuconazole concentrations may decrease (CYP3A induction by carbamazepine, phenytoin and long-acting barbiturates such as phenobarbital). The concomitant administration of CRESEMBA and carbamazepine, phenytoin and long-acting barbiturates such as phenobarbital is contraindicated.
Antibacterials
Rifampicin

(strong CYP3A4/5 inducer)

Isavuconazole:

AUCtau: ↓ 90%

Cmax: ↓ 75%

(CYP3A4/5 induction)

The concomitant administration of CRESEMBA and rifampicin is contraindicated.
Rifabutin

(strong CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may significantly decrease.

(CYP3A4/5 induction)

The concomitant administration of CRESEMBA and rifabutin is contraindicated.
Nafcillin

(moderate CY3A4/5 inducer)

Not studied.

Isavuconazole concentrations may significantly decrease.

(CYP3A4/5 induction)

The concomitant administration of CRESEMBA and nafcillin is contraindicated.
Clarithromycin

(strong CYP3A4/5 inhibitor)

Not studied.

Isavuconazole concentrations may increase.

(CYP3A4/5 inhibition)

No CRESEMBA dose adjustment necessary; caution is advised as adverse drug reactions may increase.
Antifungals
Ketoconazole

(strong CYP3A4/5 inhibitor)

Isavuconazole:

AUCtau: ↑ 422%

Cmax: ↑ 9%

(CYP3A4/5 inhibition)

The concomitant administration of CRESEMBA and ketoconazole is contraindicated.
Herbal medicines
St John’s wort

(strong CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may significantly decrease.

(CYP3A4 induction).

The concomitant administration of CRESEMBA and St John’s wort is contraindicated.
Immunosuppresants
Ciclosporin, sirolimus, tacrolimus

(CYP3A4/5 substrates)

Ciclosporin:

AUCinf: ↑ 29%

Cmax: ↑ 6%

Sirolimus:

AUCinf: ↑ 84%

Cmax: ↑ 65%

Tacrolimus:

AUCinf: ↑ 125%

Cmax: ↑ 42%

(CYP3A4 inhibition)

No CRESEMBA dose adjustment necessary.

Ciclosporin, sirolimus, tacrolimus: monitoring of plasma levels and appropriate dose adjustment if required.

Mycophenolate mofetil (MMF)

(UGT substrate)

Mycophenolic acid (MPA, active metabolite):

AUCinf: ↑ 35%

Cmax: ↓ 11%

(UGT inhibition)

No CRESEMBA dose adjustment necessary.

MMF: monitoring for MPA- related toxicities is advised.

Prednisone

(CYP3A4 substrate)

Prednisolone (active metabolite):

AUCinf: ↑ 8%

Cmax: ↓ 4%

(CYP3A4 inhibition)

Isavuconazole concentrations may decrease.

(CYP3A4/5 induction)

Co-administration should be avoided unless the potential benefit is considered to outweigh the risk.
Opioids
Short-acting opiates (alfentanil, fentanyl)

(CYP3A4/5 substrate)

Not studied.

Short-acting opiate concentrations may increase.

(CYP3A4/5 inhibition).

No CRESEMBA dose adjustment necessary.

Short-acting opiates (alfentanil, fentanyl): careful monitoring for any occurrence of drug toxicity, and dose reduction if required.

Methadone

(CYP3A4/5, 2B6, and 2C9 substrate)

S-methadone (inactive opiate isomer)

AUCinf: ↓ 35%

Cmax: ↑ 1%

40% reduction in terminal half-life

R-methadone (active opiate isomer).

AUCinf: ↓ 10%

Cmax: ↑ 4%

(CYP2B6 induction)

No CRESEMBA dose adjustment necessary.

Methadone: no dose adjustment required.

Anti-cancer
Vinca alkaloids (vincristine, vinblastine)

(P-GP substrates)

Not studied.

Vinca alkaloid concentrations may increase.

(P-GP inhibition)

No CRESEMBA dose adjustment necessary.

Vinca alkaloids: careful monitoring for any occurrence of drug toxicity, and dose reduction if required.

Cyclophosphamide

(CYP2B6 substrate)

Not studied.

Cyclophosphamide concentrations may decrease.

(CYP2B6 induction)

No CRESEMBA dose adjustment necessary.

Cyclophosphamide: careful monitoring for any occurrence of lack of efficacy, and does increase if required.

Methotrexate

(BCRP, OAT1, OAT3 substrate)

Methotrexate:

AUCinf: ↓ 3%

Cmax: ↓ 11%

7-hydroxy metabolite:

AUCinf: ↑ 29%

Cmax: ↑ 15%

(Mechanism unknown)

No CRESEMBA dose adjustment necessary.

Methotrexate: no dose adjustment required.

Other anticancer agents (daunorubicin, doxorubicin, imatinib, irinotecan, lapatinib, mitoxantrone, topotecan)

(BCRP substrates)

Not studied.

Daunorubicin, doxorubicin, imatinib, irinotecan, lapatinib, mitoxantrone, topotecan concentrations may increase.

(BCRP inhibition)

No CRESEMBA dose adjustment necessary.

Daunorubicin, doxorubicin, imatinib, irinotecan, lapatinib, mitoxantrone or topotecan: careful monitoring for any occurrence of drug toxicity, and dose reduction if required.

Antiemetics
Aprepitant

(mild CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may decrease.

(CYP3A4/5 induction)

Co-administration should be avoided unless the potential benefit is considered to outweigh the risk.
Antidiabetics
Metformin

(OCT1, OCT2 and MATE1 substrate)

Metformin:

AUCinf: ↑ 52%

Cmax: ↑ 23%

(OCT2 inhibition)

No CRESEMBA dose adjustment necessary.

Metformin: dose reduction may be required.

Repaglinide

(CYP2C8 and OATP1B1 substrate)

Repaglinide:

AUCinf: ↓ 8%

Cmax: ↓ 14%

No CRESEMBA dose adjustment necessary.

Repaglinide: no dose adjustment required.

Anticoagulants
Dabigatran etexilate

(P-gp substrate)

Not studied.

Dabigatran etexilate concentrations may increase.

(P-gp inhibition).

No CRESEMBA dose adjustment necessary.

Dabigatran etexilate has a narrow therapeutic index and should be monitored, and dose reduction if required.

Warfarin

(CYP2C9 substrate)

S-warfarin

AUCinf: ↑ 11%

Cmax: ↓ 12%

R-warfarin

AUCinf: ↑ 20%

Cmax: ↓ 7%

No CRESEMBA dose adjustment necessary.

Warfarin: no dose adjustment required.

Antiretroviral agents
Lopinavir 400 mg / Ritonavir 100 mg

(CYP3A4/5 strong inhibitors and substrates)

Lopinavir:

AUCtau: ↓ 27%

Cmax: ↓ 23%

Cmin, ss: ↓ 16%a

Ritonavir:

AUCtau: ↓ 31%

Cmax: ↓ 33%

(Mechanism unknown)

Isavuconazole:

AUCtau: ↑ 96%

Cmax: ↑ 74%

(CYP3A4/5 inhibition)

No CRESEMBA dose adjustment necessary; caution is advised as adverse drug reactions may increase.

Lopinavir/ritonavir: no dose adjustment for lopinavir 400 mg/ritonavir 100 mg every 12 hours required, but careful monitoring for any occurrence of lack of anti-viral efficacy.

Ritonavir (at doses > 200 mg every 12 hours)

(strong CYP3A4/5 inducer)

Not studied.

Ritonavir at high doses may significantly decrease isavuconazole concentrations.

(CYP3A4/5 induction)

The concomitant administration of CRESEMBA and high doses of ritonavir (> 200 mg every 12 hours) is contraindicated.
Efavirenz

(CYP3A4/5 moderate inducer and CYP2B6 substrate)

Not studied.

Efavirenz concentrations may decrease.

(CYP2B6 induction)

Isavuconazole drug concentrations may significantly decrease.

(CYP3A4/5 induction)

The concomitant administration of CRESEMBA and efavirenz is contraindicated. .
Etravirine

(moderate CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may significantly decrease.

(CYP3A4/5 induction)

The concomitant administration of CRESEMBA and etravirine is contraindicated.
Indinavir

(CYP3A4/5 strong inhibitor and substrate)

Indinavir:b

AUCinf: ↓ 36%

Cmax: ↓ 52%

(Mechanism unknown)

Isavuconazole concentrations may increase.

(CYP3A4/5 inhibition)

No CRESEMBA dose adjustment necessary; caution is advised as adverse drug reactions may increase.

Indinavir: careful monitoring for any occurrence of lack of antiviral efficacy, and does increase if required.

Saquinavir

(strong CYP3A4 inhibitor)

Not studied.

Saquinavir concentrations may decrease (as observed with lopinavir/ritonavir) or increase

(CYP3A4 inhibition).

Isavuconazole concentrations may increase.

(CYP3A4/5 inhibition).

No CRESEMBA dose adjustment necessary; caution is advised as adverse drug reactions may increase.

Saquinavir: careful monitoring for any occurrence of drug toxicity and /or lack of anti-viral efficacy, and dose adjustment if required

Other protease inhibitors (e.g., amprenavir, nelfinavir)

(CYP3A4/5 strong or moderate inhibitors and substrates)

Not studied.

Protease inhibitor concentrations may decrease (as observed with lopinavir/ritonavir) or increase.

(CYP3A4 inhibition)

Isavuconazole concentrations may increase.

(CYP3A4/5 inhibition).

No CRESEMBA dose adjustment necessary.

Protease inhibitors: careful monitoring for any occurrence of drug toxicity and /or lack of antiviral efficacy, and dose adjustment if required.

Other NNRTI (e.g., delavirdine, and nevirapine)

(CYP3A4/5 and 2B6 inducers and substrates)

Not studied.

NNRTI concentrations may decrease (CYP2B6 induction by isavuconazole) or increase.

(CYP3A4/5 inhibition)

No CRESEMBA dose adjustment necessary.

NNRTIs: careful monitoring for any occurrence of drug toxicity and/or lack of anti-viral efficacy, and dose adjustment if required.

Antiacids
Esomeprazole

(CYP2C19 substrate and gastric pH ↑)

Isavuconazole:

AUCtau: ↑ 8%

Cmax: ↑ 5%

No CRESEMBA dose adjustment necessary.

Esomeprazole: no dose adjustment required.

Omeprazole

(CYP2C19 substrate and gastric pH ↑)

Omeprazole:

AUCinf: ↓ 11%

Cmax: ↓ 23%

No CRESEMBA dose adjustment necessary.

Omeprazole: no dose adjustment required.

Lipid-lowering agents
Atorvastatin and other statins (CYP3A4 substrates e.g., simvastatin, lovastatin, rosuvastatin)

(CYP3A4/5 and/or BCRP substrates)

Atorvastatin :

AUCinf: ↑ 37%

Cmax: ↑ 3%

Other statins were not studied.

Statins concentrations may increase.

(CYP3A4/5 or BCRP inhibition)

No CRESEMBA dose adjustment necessary.

Based on results with atorvastatin, no statin dose adjustment required. Monitoring of adverse reactions typical of statins is advised.

Pioglitazone

(mild CYP3A4/5 inducer)

Not studied.

Isavuconazole concentrations may decrease.

(CYP3A4/5 induction)

Co-administration should be avoided unless the potential benefit is considered to outweigh the risk.
Antiarrhythmics
Digoxin

(P-GP substrate)

Digoxin:

AUCinf: ↑ 25%

Cmax: ↑ 33%

(P-GP inhibition)

No CRESEMBA dose adjustment necessary.

Digoxin: serum digoxin concentrations should be monitored and used for titration of the digoxin dose.

Oral contraceptives
Ethinyloestradiol and norethindrone

(CYP3A4/5 substrates)

Ethinyloestradiol

AUCinf: ↑ 8%

Cmax: ↑ 14%

Norethindrone

AUCinf: ↑ 16%

Cmax: ↑ 6%

No CRESEMBA dose adjustment necessary.

Ethinyloestradiol and norethindrone: no dose adjustment required.

Antitussives
Dextromethorphan

(CYP2D6 substrate)

Dextromethorphan:

AUCinf: ↑ 18%

Cmax: ↑ 17%

Dextrorphan (active metabolite):

AUCinf: ↑ 4%

Cmax: ↓ 2%

No CRESEMBA dose adjustment necessary.

Dextromethorphan: no dose adjustment required.

Benzodiazepines
Midazolam

(CYP3A4/5 substrate)

Oral midazolam:

AUCinf: ↑ 103%

Cmax: ↑ 72%

(CYP3A4 inhibition)

No CRESEMBA dose adjustment necessary.

Midazolam: careful monitoring of clinical signs and symptoms recommended, and dose reduction if required.

Antigout agent
Colchicine

(P-GP substrate)

Not studied.

Colchicine concentrations may increase.

(P-GP inhibition)

No CRESEMBA dose adjustment necessary.

Colchicine has a narrow therapeutic index and should be monitored, dose reduction if required.

Natural products
Caffeine

(CYP1A2 substrate)

Caffeine:

AUCinf: ↑ 4%

Cmax: ↓ 1%

No CRESEMBA dose adjustment necessary.

Caffeine: no dose adjustment required.

Smoking cessation aids
Bupropion

(CYP2B6 substrate)

Bupropion:

AUCinf: ↓ 42%

Cmax: ↓ 31%

(CYP2B6 induction)

No CRESEMBA dose adjustment necessary.

Bupropion: dose increase if required.

Pregnancy & Lactation of Isavuconazole

FDA pregnancy risk category C

Pregnancy

There are no data from the use of pregnant women.

It must not be used during pregnancy except in patients with severe or potentially life-threatening fungal infections, in whom isavuconazole may be used if the anticipated benefits outweigh the possible risks to the fetus.

Lactation

Isavuconazole is not recommended for women of childbearing potential who are not using contraception. Available pharmacodynamic/toxicological data in animals have shown excretion of isavuconazole/metabolites in milk

There are no data on the effect of isavuconazole on human fertility. Studies in animals did not show impairment of fertility in male or female rats

References

Posaconazole

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