Hikma launches Posaconazole Oral Suspension in the US

London, 3 April 2023 – Hikma Pharmaceuticals PLC (Hikma), the multinational pharmaceutical company, announces it has launched Posaconazole Oral Suspension in 40mg/mL dose. The product, launched in the US, will be the first generic on the market, broadening the choice of medicine available to doctors and patients.

Press Release Product 3 April 2023

text 1

Posaconazole Oral Suspension is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy in adult and pediatric patients aged 13 years and older. Posaconazole oral suspension is also indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in adult and pediatric patients aged 13 years and older.

According to IQVIA, US sales of Posaconazole Oral Suspension, 40mg/mL were approximately $16 million in the 12 months ending January 2023.

This product has been approved for marketing in the United States by the US FDA.  This product approval does not confer the right on Hikma, or any other party, to market this product outside the United States.

 

Important Safety Information for Posaconazole Oral Suspension, 40mg/mL:

CONTRAINDICATIONS

  • Hypersensitivity

Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

  • Use With Sirolimus

Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity.

  • QT Prolongation With Concomitant Use With CYP3A4 Substrates

Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes.

  • HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4

Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis.

  • Use With Ergot Alkaloids

Posaconazole may increase the plasma concentrations of ergot alkaloids, which may lead to ergotism.

  • Use With Venetoclax

Coadministration with venetoclax at initiation and at the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome (TLS).

WARNINGS AND PRECAUTIONS

  • Calcineurin-Inhibitor Drug Interactions

Concomitant administration with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors.

Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

  • Arrhythmias and QT Prolongation

Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole.

Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.

  • Electrolyte Disturbances

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

  • Hepatic Toxicity

Hepatic reactions have been reported in clinical trials. Cases of more severe hepatic reactions, including cholestasis or hepatic failure (including deaths), have been reported in patients with serious underlying medical conditions during treatment with posaconazole. These severe hepatic reactions were seen primarily in clinical trial subjects receiving 800 mg posaconazole oral suspension daily (400 mg BID or 200 mg QID).

Liver function should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be 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 posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.

  • Renal Impairment

Patients with severe renal impairment should be monitored closely for breakthrough fungal infections.

  • Midazolam Toxicity

Concomitant administration with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam, and benzodiazepine receptor antagonists must be available to reverse these effects.

  • Vincristine Toxicity

Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

  • Breakthrough Fungal Infections

Patients with severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole.

  • Venetoclax Toxicity

Concomitant administration may increase venetoclax toxicities, including the risk of TLS, neutropenia and serious infections. In patients with CLL/SLL, administration during the initiation and ramp-up phase of venetoclax is contraindicated. Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients.

For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax. See the Full Prescribing Information for venetoclax for dosing instructions.

ADVERSE REACTIONS

The following serious and otherwise important adverse reactions are discussed in detail in the Full Prescribing Information for posaconazole oral suspension:

  • Hypersensitivity
  • Arrhythmias and QT Prolongation
  • Hepatic Toxicity

In prophylaxis clinical trials, the most frequently reported adverse reactions (>30%) were fever, diarrhea and nausea. In studies of HIV-infected patients with oropharyngeal Candida (OPC) and refractory OPC (rOPC), the most common adverse reactions were fever, diarrhea, nausea, headache, vomiting and coughing. Adverse reactions were reported more frequently in study patients with rOPC.

Advise patients to inform their physician immediately if they develop severe diarrhea or vomiting, if they notice swelling in an arm or leg or if they experience shortness of breath.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

DRUG INTERACTIONS

Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole.

  • Immunosuppressants Metabolized by CYP3A4

Sirolimus: Posaconazole is contraindicated with sirolimus.

Tacrolimus: At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly.

Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. Reduce the cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly.

  • CPY3A4 Substrates

Concomitant administration of posaconazole with CYP3A4 substrates is contraindicated.

  • HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4

Posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4.

  • Ergot Alkaloids

Posaconazole is contraindicated with ergot alkaloids.

  • Benzodiazepines Metabolized by CYP3A4

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4, and benzodiazepine receptor antagonists must be available to reverse these effects.

  • Anti-HIV Drugs

Efavirenz: Avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.

Ritonavir and Atazanavir: Monitor patients frequently for adverse effects and toxicity of ritonavir and atazanavir during coadministration with posaconazole.

Fosamprenavir: If concomitant administration of fosamprenavir with posaconazole is required, close monitoring for breakthrough fungal infections is recommended.

  • Rifabutin

Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. If concomitant administration is required, monitor the patient closely for breakthrough fungal infections. Frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations is also recommended.

  • Phenytoin

Concomitant use of posaconazole and phenytoin should be avoided unless the benefit outweighs the risk. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Monitor phenytoin concentrations frequently and consider reducing the dose of phenytoin.

  • Gastric Acid Suppressors/Neutralizers

Avoid concomitant use of cimetidine and esomeprazole with posaconazole oral suspension unless the benefit outweighs the risks. If concomitant administration is required, monitor patient closely for breakthrough fungal infections.

  • Vinca Alkaloids

Concomitant administrations of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions. Posaconazole may increase the plasma concentrations of vinca alkaloids, which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

  • Calcium Channel Blockers Metabolized by CYP3A4

Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration with posaconazole. Dose reduction of calcium channel blockers may be needed.

  • Digoxin

Monitoring of digoxin plasma concentrations is recommended during coadministration with posaconazole.

  • Gastrointestinal Motility Agents

Monitor patients closely for breakthrough fungal infections during concomitant administration with metoclopramide. No dosage adjustment of posaconazole oral suspension is required when loperamide and posaconazole oral suspension are used concomitantly.

  • Glipizide

Monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

  • Venetoclax

Concomitant use of venetoclax with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities. See the Full Prescribing Information for venetoclax for more information on dosing instructions and the extent of increase in venetoclax exposure.

USE IN SPECIFIC POPULATIONS

  • Pregnancy

Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women.

  • Lactation

There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition.

  • Pediatric Use

The safety and effectiveness of posaconazole in pediatric patients younger than 13 years have not been established.

  • Geriatric Use

No overall differences in pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

  • Renal Impairment

Patients with severe renal impairment should be monitored closely for breakthrough fungal infections.

  • Weight

Patients weighing >120 kg should be monitored closely for breakthrough fungal infections.

DOSAGE AND ADMINISTRATION

Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension due to the differences in dosing of each formulation.

Administer with a full meal (or liquid nutritional supplement or acidic carbonated beverage in patients who cannot eat a full meal). For details, see the Full Prescribing Information for posaconazole oral suspension.

Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. Monitor patients who require these drugs closely for breakthrough fungal infections.

 

For more information, please see the Full Prescribing Information, including the Boxed Warning.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit https://www.fda.gov/medwatch or call 1-800-FDA-1088.

Manufactured by: West-Ward Columbus Inc., Columbus, OH 43228

Distributed by: Hikma Pharmaceuticals USA Inc., Berkeley Heights, NJ 07922

Important notice for users

You are about to access Hikma historic archive material. Any reference in these archives to Hikma products or their uses may not reflect current medical knowledge and should not be used as a source of information on the present product label, efficacy data, or safety data. Please refer to your approved national product label (SmPC) for current product information.

I have read this warning and will not be using any of the contained product information for clinical purposes.