Last Updated on eMC 26-05-2017 View medicine  | Merck Sharp & Dohme Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Date of revision of text on the SPC:21-04-2017

Legal Category:POM

Black Triangle (CHM): NO

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·        4.4         Special warnings and precautions for use

The following text has been added under a new subheading of ‘Drug Interactions’:

 

‘Vincristine Toxicity

Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options (see section 4.5).’

 

There have been a number of minor additional editorial changes to this section.

 

·        4.5         Interaction with other medicinal products and other forms of interaction

 

The existing text:

‘Posaconazole may increase the plasma concentration of vinca alkaloids (e.g. vincristine and vinblastine), which may lead to neurotoxicity. Therefore, concomitant use of posaconazole and vinca alkaloids should be avoided unless the benefit to the patient outweighs the risk. If co-administered, then it is recommended that dose adjustment of vinca alkaloids be considered.’

 

Has been replaced with:

‘Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions (see section 4.4). 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.’

 

Reasons for adding or updating:

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:21-07-2016

Legal Category:POM

Black Triangle (CHM): NO

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Section 5.1 and Section 5.2 have been updated to reflect the study P03579/PN032 results

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration

Date of revision of text on the SPC:22-07-2016

Legal Category:POM

Black Triangle (CHM): NO

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The changes made to the SmPC are as follows:

 

·        Section 4.2 - Posology and method of administration:

 

The current statement on non-interchangeability has been replaced with the following text at the start of this section:

 

‘Non-Interchangeability between Noxafil Tablets and Noxafil Oral Suspension

 

The tablet and oral suspension are not to be used interchangeably due to the differences between these two formulations in frequency of dosing, administration with food and plasma drug concentration achieved. Therefore, follow the specific dosage recommendations for each formulation.’

 

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Correction of spelling/typing errors

Date of revision of text on the SPC:09-06-2015

Legal Category:POM

Black Triangle (CHM): NO

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The changes made to the SmPC are as follows:

·        Section 4.8 - Undesirable effects:

o   Correction of frequency of AE tachypnoea (was listed as rare, corrected to uncommon)
o   Minor edits
o   Correction of subheading ‘Reporting of suspected adverse reactions’

 

 

 

 

Reasons for adding or updating:

  • Change to section 1 - Name of the medicinal product
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:18-09-2014

Legal Category:POM

Black Triangle (CHM): NO

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·        Section 4.2 – Posology and method of administration:

Noxafil 300 mg concentrate for solution for infusion introduced into posology paragraph.

Administrative change to the unit dose millilitres from ml to mL

Special Populations (paediatrics) – reference to the safety and efficacy of Noxafil in adolescents deleted.

·        Section 4.4 – Special warnings as precautions for use:

Paragraph on the use of Midazolam and other benzodiazepines metabolised by CYP3A4 added – dose adjustment should be considered.

·        Section 4.5 – Interaction with other medicinal products…:

Administrative changes: basic formatting of text (changed to italics) to harmonise with EU text, abbreviations BID and QD replaced with twice daily and once daily.

Reference to section 4.4 added at the end of paragraph “Midazolam and other benzodiazepines metabolised by CYP3A4” added, to link sections in SmPC.

·        Section 4.7 – Effects on ability to drive and use machines:

Deletion of sentence “No studies on the effects of Posaconazole on the ability to drive and use machines have been performed”

·        Section 4.8 – Undesirable effects:

Administrative change: BID replaced with twice daily

Table 2. Adverse reactions by body system and frequency updated with new side effects

Blood and Lymphatic system disorders : Uncommon – Splenic infarction; Metabolism and nutrition disorders: Common – decreased appetite, hypomagnesaemia; Uncommon – hypoglycaemia; Psychiatric disorders: Uncommon – abnormal dreams, confusional state, sleep disorder; Not known – confusional state; Nervous system disorders: Common – dysgeusia; Eye disorders: Uncommon – photophobia, visual acuity reduced; Vascular disorders; Common – hypertension; Respiratory thoracic and mediastinal disorders; Uncommon – nasal congestion, tachypnoea, Gastro-intestinal disorders: Common – anorectal discomfort, Uncommon – abdominal distension, enteritis, epigastric discomfort, eructation; Hepatobiliary disorders: Uncommon – cholestasis, hepatic toxicity, hepatic function abnormal; Rare: cholestasisSkin and subcutaneous tissue disorders: Uncommon – dermatitis, erythema, petechiae; Muscoskeletal and connective tissue disorders: Uncommon – neck pain, musculoskeletal pain; General disorders and administration site conditions: Uncommon – chest discomfort, drug intolerance, feeling jittery; Investigations: blood phosphorus decreased, chest x-ray abnormal.

Footnote added to end of table*Based on adverse reactions observed with the oral suspension, gastro-resistant tablets, and concentrate for solution for infusion.

Reporting of suspected adverse reactions updated – editorial change with replacement of “website” to “at”

·        Section 5.1 – Pharmacodynamic properties:

Administrative changes: basic formatting of text (changed to italics) to harmonise with EU text, abbreviations BID and QD replaced with twice daily and once daily.

·        Section 5.2 – Pharmacokinetic properties:

New paragraph on weight added – weight >120 kg may have lower posaconazole exposure…

Editorial change – insufficiency replaced with impairment

·        Section 10 – Date of revision of text 18 September 2014

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:23-04-2014

Legal Category:POM

Black Triangle (CHM): NO

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Section 4.1: Therapeutic indications-

-          Noxafil updated to Noxafil oral suspension, editorial changes.
Section 4.2: Posology and method of administration-
-          paragraph added to align with Noxafil tablet SPC - Noxafil is also available as 100 mg gastro resistant tablets. Noxafil tablets are the preferred formulation.
-          Editorial changes to Table 1. Recommended dose according to indication
-          Paediatric population – and adolescents added
Section 4.4: Special warnings and precautions for use
-          editorial change in hepatic toxicity paragraph – hepatic insufficiency changed to hepatic impairment
-          Monitoring of hepatic function – sentence added – Liver function tests should be evaluated at the start of and during the course of posaconazole therapy.

Section 4.5: Interaction with other medicinal products and other forms of interaction
-          Fosamprenavir – oral suspension added after posaconazole
-          Phenytoin added as a heading
-          Headings Alcohol, Herbal medicinal products and Smoking deleted from section 4.4

Section 4.8: Undesirable effects
-          paragraph added – The safety of posaconazole tablet has been assessed in 336 patients and healthy volunteers enrolled in clinical trials. The safety profile of tablets was similar to that of the oral Suspension

-          Tabulated list of Adverse reactions – aligned with Noxafil 100 mg Tablets

-          Metabolism and nutrition disorders: Common: hypokalaemia; Uncommon: hyperglycaemia

-          Nervous system disorders: Uncommon: aphasia, insomnia

-          Cardiac disorders: Uncommon: bradycardia, superventricular extrasystoles, tachycardia

-          Vascular disorders: Uncommon: vasculitis

-          Respiratory, thoracic and mediastinal disorders: Uncommon: cough, epistaxis, hiccups, pleuritic pain

-          Gastrointestinal disorders: Very Common: nausea; Common: constipation; Uncommon: Gastrooesophageal reflux disease, oedema mouth

-          Skin and subcutaneous tissue disorders: Common: rash, pruritis

-          Musculoskeletal and connective tissue disorders: Uncommon: pain in extremity

-          General disorders and administration site conditions: Uncommon: mucosal inflammation

-          Reporting of suspected adverse reactions paragraph added.
Section 5.1: Pharmacodynamic properties

-          ECOFF Values for Aspergillus spp – added -  ECOFF values do not equate to clinical breakpoints. Also added study number 0041

Section 5.3: Preclinical safety data
-          Echocardiography revealed no exposures concentrations….achieved with the human dose Date of revision of text:  23 April 2014

Reasons for adding or updating:

  • Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC:19-09-2013

Legal Category:POM

Black Triangle (CHM): NO

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SmPC update of section 5.1 by inclusion of Epidemiology Cut-off Values (ECOFFs) for Aspergillus spp.

5.1       Pharmacodynamic properties

 

…............

Resistance

Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.

 

Epidemiological Cut-off (ECOFF) Values for Aspergillus spp.

The ECOFF values for posaconazole, which distinguish the wild type population from isolates with acquired resistance have been determined by EUCAST methodology.

 

EUCAST ECOFF values:

·             Aspergillus flavus: 0.5 mg/L

·             Aspergillus fumigatus: 0.25 mg/L

·             Aspergillus nidulans: 0.5 mg/L

·             Aspergillus niger: 0.5 mg/L

·             Aspergillus terreus: 0.25 mg/L

 

There are currently insufficient data to set clinical breakpoints for Aspergillus spp.

 

Reasons for adding or updating:

  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 10 date of revision of the text
  • Correction of spelling/typing errors

Date of revision of text on the SPC:23-08-2012

Legal Category:POM

Black Triangle (CHM): NO

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The changes made are as follows:

1.        Section 5.1 (Pharmacodynamic properties): addition of EUCAST breakpoints for posaconazole against Candida albicans, Candida tropicalis and Candida parapsilosis. We have also stated the there is currently insufficient data to set breakpoints for the other Candida species.
2.       Section 10 (Date of revision of the text): has been updated.
3.       Correction of some formatting errors in document.

Reasons for adding or updating:

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:19-12-2011

Legal Category:POM

Black Triangle (CHM): NO

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4.5 Interaction with other medicinal products and other forms of interaction

Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Repeat dose administration of fosamprenavir (700 mg BID x 10 days) decreased the Cmax and AUC of posaconazole (200 mg QD on the 1st day, 200 mg BID on the 2nd day, then 400 mg BID x 8 Days) by 21 % and 23 %, respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with ritonavir is unknown.

Paediatric population

Interaction studies have only been performed in adults.

There have also been typograpical changes made throughout the document.

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:06-10-2011

Legal Category:POM

Black Triangle (CHM): NO

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Amendment due to marketing authorisation holder change to MSD.

Reasons for adding or updating:

  • Removal of Black Triangle

Date of revision of text on the SPC:30-09-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Removal of inverted black triangle symbol.

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.7 - Effects on Ability to Drive and Use Machines
  • Change to section 4.8 - Undesirable Effects
  • Change to section 4.9 - Overdose
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 6. 6 - Instructions for use, handling and disposal

Date of revision of text on the SPC:30-09-2010

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



The following sections of the SmPC have been updated:

2 - Glucose is mentioned as an excipient in the medicinal product.

4.2 - Some new headings have been added. Information on patients with severe gastrointestinal dysfunction has been removed and information on paediatric population has been updated. New section on method of administration added.

4.4 - Some new headings added. New information about Gastrointestinal dysfunction added. Information about Rifabutin deleted.

4.5 - Interactions with food, Alcohol, Herbal medicinal products and smoking added

4.6 - Headings, 'Pregnancy and Breast-feeding', have been added and an additional section on fertility including information from preclinical studies has also been added. The following statement is included: There is no clinical experience assessing the impact of posaconazole on fertility in humans.

 

4.7 - The following has been added to this section:

 

Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with posaconazole use, which potentially may affect driving/operating machinery, caution needs to be used.

 

4.8 - Table headings and other minor changes updated but no additional adverse events.

4.9 - Has been updated with the following statement:

 

There is no special treatment available in the case of overdose with posaconazole. Supportive care may be considered.

 

5.2 - New heading added.

6.6 - Updated to include disposal in accordance with local requirements.

Reasons for adding or updating:

  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:23-11-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

4.6
Title of Pregnancy and lactation changed to "Fertility, pregnancy and lactation"

4.8
Addition of "not known (cannot be estimated from the available data)" to the header of Table 2.
Addition of "not known" and "confusional state" to the psychiatric disorders section of Table 2.

10.0
Change of date from "28 October 2009" to "23 November 2009"

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:28-10-2009

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



4.2   Table 1: Title Row: Addition of (see section 5.2) under Dose duration of therapy.
        Tabel 1: Row 1:Change of "Dose from 400mg (10ml) twice a day...." to 2"00mg (5ml) four times a day.  Alternatively, patients who can tolerate food or a nutritional supplement may take 400mg (10ml) twice a day during or immediately followign a meal or nutritional suppliment"
        Table 1: Row 2: Addition of "during or immediately after" before "meal..."
        Table 1: Row 3: Addition of "during or immediately after" before "meal..."
        Paragraph 5: Change of imparment to insufficiency, and change of sentence to explain the same thing (limited data on effect of hepatic insufficiency demonstrates an increase in plasma exposure) and adds that this does not suggest that dose adjustment is necessary.
4.4    PAragraph 2: last sentence replaced with "posaconazole shoudl be used with caution in patients with hepatic insufficiency due to limited clinical experience and the possibility that posaconazole plasma levels may be higher in these pateints (see section 5.2)"
4.5    H2 receptor antag paragraph: Removal of text from "Concomintant use of posaconazole and cimetidine.." and replaced with "Co-administration os posaconazole with H2 receptor antagonists shoudl be avoided if possible. Similarly, administration of 400mg posaconazole with esomeprazole (40mg daily) decreased mean Cmax and AUC by 46% and 32% respectively, compared to dosing with 400mg posaconazole alone.  co-administration of posaconazole with proton pump inhibitors should be avoided if possible"
5.2    Effect of Food paragraph: Replacement of whole paragraph with "The absorption of posaconazole was significantly increased when posaconazole 400 mg (QD) was administered during and immediately after the consumption of a high fat meal (~ 50 grams fat) compared to administration before a meal, with Cmax and AUC increasing by approximately 330 % and 360 %, respectively. The AUC of posaconazole is: 4 times greater when administered with a high-fat meal (~ 50 grams fat) and about 2.6 times greater when administered during a non-fat meal or nutritional supplement (14 grams fat) relative to the fasted state (see sections 4.2 and 4.5)."

5.2    Hepatic "inpairment" changed to insufficiency and whole paragraph replaced
10.    Date of revision changed from 4 December 2008 to 28 October 2009

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:04-12-2008

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Section 4.8 - Undesirable Effects - complete section updated

Section 10 - updated date of revision of text

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-03-2008

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.4

 

From:

Hepatic toxicity: In clinical trials, there were reports of hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions including cholestasis or hepatic failure were reported in patients with serious underlying medical conditions (e.g. hematologic malignancy) during treatment with posaconazole.

Posaconazole should be used with caution in patients with severe hepatic impairment. In these patients, the prolonged elimination half-life may lead to increased exposure.

 

To:

 

Hepatic toxicity: Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been reported.

Posaconazole should be used with caution in patients with severe hepatic impairment. In these patients, the prolonged elimination half-life may lead to increased exposure.

 

Section 4.8

 

The following sentence has been added at the end of this section:

 

During post marketing surveillance severe hepatic injury with fatal outcome has been reported (see section 4.4).

 

Section 10

 

Date of revision of text updated

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable Effects
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-10-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.2

 

Sentence beginning "Use in renal impairment" changed from:

 

(see sections 4.4 and 5.2)

 

Changed to:

 

(see section 5.2)

 

Section 4.4

 

Paragraph beginning "Rifamycin antibacterials (rifampicin, rifabutin) ..." the drug "efavirenz" has been added to this list.

 

Section 4.5


After paragraph 2, the following paragraph has been added:

 

Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk.

 

The paragraph headed: Effects of posaconazole on other medicinal products¡± has been changed from:

 

Posaconazole is an inhibitor of CYP3A4. Posaconazole 200 mg once daily increased the exposure (AUC) of the CYP3A4 substrate midazolam after intravenous administration by 83 %. Caution is advised during co-administration of CYP3A4 substrates administered intravenously and the dose of the CYP3A4 substrate may need to be reduced. The effect of posaconazole on plasma concentrations of orally administered CYP3A4 substrates is not known, but a much larger effect than that observed for intravenously administered substrates could be expected. If Noxafil is used concomitantly with CYP3A4 substrates that are administered orally, and for which an increase in plasma concentrations may be associated with unacceptable adverse events, plasma concentrations of the CYP3A4 substrate or adverse events should be closely monitored and the dose adjusted as needed.

 

To:

 

Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4 substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co-administration of posaconazole with CYP3A4 substrates administered intravenously and the dose of the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4 substrates that are administered orally, and for which an increase in plasma concentrations may be associated with unacceptable adverse events, plasma concentrations of the CYP3A4 substrate and/or adverse events should be closely monitored and the dose adjusted as needed. Several of the interaction studies were conducted in healthy volunteers in whom a higher exposure to posaconazole occurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4 substrates in patients might be somewhat lower than that observed in healthy volunteers, and is expected to be variable between patients due to the variable posaconazole exposure in patients. The effect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also be variable within a patient, unless posaconazole is administered in a strictly standardised way with food, given the large food effect on posaconazole exposure (see section 5.2).

 

The paragraph relating to "Sirolimus" has been changed from:

 

Sirolimus: Posaconazole may increase the plasma concentration of sirolimus. Monitoring of sirolimus blood levels should be performed upon initiation, during co-administration, and upon discontinuation of posaconazole treatment. The dose of sirolimus should be adjusted as necessary.

 

To:

 

Sirolimus: Repeat dose administration of oral posaconazole (400 mg twice daily for 16 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range 3.1 to 17.5-fold), respectively, in healthy subjects. The effect of posaconazole on sirolimus in patients is unknown, but is expected to be variable due to the variable posaconazole exposure in patients. Co-administration of posaconazole with sirolimus is not recommended and should be avoided whenever possible. If it is considered that co-administration is unavoidable, then it is recommended that the dose of sirolimus should be greatly reduced at the time of initiation of posaconazole therapy and that there should be very frequent monitoring of trough concentrations of sirolimus in whole blood. Sirolimus concentrations should be measured upon initiation, during co-administration, and at discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly. It should be noted that the relationship between sirolimus trough concentration and AUC is changed during co-administration with posaconazole. As a result, sirolimus trough concentrations that fall within the usual therapeutic range may result in sub-therapeutic levels. Therefore trough concentrations that fall in the upper part of the usual therapeutic range should be targetted and careful attention should be paid to clinical signs and symptoms, laboratory parameters and tissue biopsies.

 

The paragraph titled to Antiretroviral agents has been changed from:

 

Antiretroviral agents: As HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are CYP3A4 substrates, it is expected that posaconazole will increase plasma levels of these antiretroviral agents. Patients should be carefully monitored for any occurrence of toxicity during the co-administration of posaconazole and these agents.

 

To:

 

HIV Protease Inhibitors: As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase plasma levels of these antiretroviral agents. Following co-administration of oral posaconazole (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy subjects Cmax and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold), respectively. Following co-administration of oral posaconazole (400 mg twice daily) with atazanavir and ritonavir (300/100 mg once daily) for 7 days in healthy subjects Cmax and AUC of atazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. The addition of posaconazole to therapy with atazanavir or with atazanavir plus ritonavir was associated with increases in plasma bilirubin levels. Frequent monitoring for adverse events and toxicity related to antiretroviral agents that are substrates of CYP3A4 is recommended during co-administration with posaconazole.

 

The paragraph relating to: Midazolam and other benzodiazepines metabolised by CYP3A4: has been changed from:

 

Posaconazole 200 mg orally once daily increased the AUC of midazolam by 83 % following intravenous administration. Due to the inhibition of intestinal CYP3A4 by posaconazole, an even greater effect of posaconazole on the AUC of midazolam is expected following oral administration. Dose adjustments should be considered for all benzodiazepines that are metabolised through CYP3A4 (e.g. midazolam, triazolam, alprazolam) during co-administration with posaconazole.

 

To:

 

In a study in healthy volunteers posaconazole (200 mg once daily for 10 days) increased the exposure (AUC) of IV midazolam (0.05 mg/kg) by 83 %. In another study in healthy volunteers, repeat dose administration of oral posaconazole (200 mg twice daily for 7 days) increased the Cmax and AUC of IV midazolam (0.4 mg single dose) by an average of 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazole 400 mg twice daily for 7 days increased the IV midazolam Cmax and AUC by 1.6 and 6.2-fold (range 1.6 to 7.6-fold), respectively. Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mg single oral dose) by 2.2 and 4.5-fold, respectively. In addition, oral posaconazole (200 mg or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 8-10 hours during co-administration.

Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered when posaconazole is administered concomitantly with any benzodiazepine that is metabolised by CYP3A4 (e.g. midazolam, triazolam, alprazolam).

 

Section 4.8

 

In the header section of Table 2, the incidence rates have been amended from:

 

Common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000

 

To:

 

Common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000)

 

Section 10


Date of revision of text has been updated

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-10-2006

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.1

 

First sentence – removal of the word “invasive”.

 

Additional indication:

 

-         Oropharyngeal candidiasis: as first-line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor.

 

Following has been added to this section:

 

Noxafil is also indicated for prophylaxis of invasive fungal infections in the following patients:

 

-         Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections;

-         Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high risk of developing invasive fungal infections.

 

Section 4.2

 

First sentence changed from:

 

Treatment should be initiated by a physician experienced in the management of invasive fungal infections.

 

To:

 

Treatment should be initiated by a physician experienced in the management of fungal infections or in the supportive care in the high risk patients for which posaconazole is indicated as prophylaxis.

 

The following paragraph’s re: dosing have been removed:

 

Noxafil should be administered at a dose of 400 mg (10 ml) twice a day with a meal, or with 240 ml of a nutritional supplement. In patients who cannot tolerate a meal or a nutritional supplement, Noxafil should be administered at a dose of 200 mg (5 ml) four times a day. The oral suspension must be shaken well before use.

 

Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.

 

And replaced with Table 1 and the following sentences:

 

There are limited pharmacokinetic data in patients with severe gastrointestinal dysfunction (such as severe diarrhoea). Patients who have severe diarrhoea or vomiting should be monitored closely for breakthrough fungal infections.

 

The oral suspension must be shaken well before use.

 

Section 4.4

 

Second paragraph changed from:

 

Hepatic toxicity: In clinical trials, there were reports of hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin) during treatment with posaconazole. These hepatic reactions were noted to occur mostly in patients with serious underlying medical conditions (e.g. haematological malignancy) and rarely required discontinuation of therapy. Elevated liver function tests were reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Posaconazole should be used with caution in patients with severe hepatic impairment. In these patients, the prolonged elimination half-life may lead to increased exposure.

 

To:

 

Hepatic toxicity: In clinical trials, there were reports of hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions including cholestasis or hepatic failure were reported in patients with serious underlying medical conditions (e.g. hematologic malignancy) during treatment with posaconazole.

 

The following sentence changed from:

 

This medicinal product contains approximately 7 g of glucose in the daily recommended dose. Patients with glucose-galactose malabsorption should not take this medicine.

 

To:

 

This medicinal product contains approximately 1.75 g of glucose per 5ml of suspension. Patients with glucose-galactose malabsorption should not take this medicine.

 

Section 4.5

 

Second paragraph, 1st sentence changed from:

 

Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole by 57 % and 51 %, respectively.

 

To:

 

Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively.

 

Fourth Paragraph, third sentence changed from:

 

The effect of other H2 receptor antagonists and proton pump inhibitors that may suppress gastric acidity for several hours on plasma levels of posaconazole has not been studied but a reduction in bioavailability may occur so that co-administration should be avoided if possible.

 

To:

 

The effect of other H2 receptor antagonists (eg. famotidine, ranitidine) and proton pump inhibitors (eg. omeprazole) that may suppress gastric acidity for several hours on plasma levels of posaconazole has not been studied but a reduction in bioavailability may occur so that co-administration should be avoided if possible.

 

Eleventh Paragraph changed from:

 

Ciclosporin: In heart transplant patients on stable doses of ciclosporin, posaconazole 200 mg once daily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporin levels resulting in serious adverse events, including nephrotoxicity were reported in clinical efficacy studies. Monitoring of ciclosporin blood levels should be performed upon initiation, during co-administration, and upon discontinuation of posaconazole treatment, with adjustment of ciclosporin doses as necessary.

 

To:

 

Ciclosporin: In heart transplant patients on stable doses of ciclosporin, posaconazole 200 mg once daily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporin levels resulting in serious adverse events, including nephrotoxicity and one fatal case of leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e.g. to about three quarters of the current dose). Thereafter blood levels of ciclosporin should be monitored carefully during co-administration, and upon discontinuation of posaconazole treatment, and the dose of ciclosporin should be adjusted as necessary.

 

Twelfth paragraph changed from:

 

Tacrolimus: Posaconazole increased Cmax and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121 % and 358 %, respectively. Clinically significant interactions resulting in hospitalisation and/or posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole treatment in patients already receiving tacrolimus, the dose of tacrolimus dose should be reduced (e.g. to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during co-administration, and upon discontinuation of posaconazole, and the dose of tacrolimus should be adjusted as necessary.

 

To:

 

Tacrolimus: Posaconazole increased Cmax and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121 % and 358 %, respectively. Clinically significant interactions resulting in hospitalisation and/or posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during co-administration, and upon discontinuation of posaconazole, and the dose of tacrolimus should be adjusted as necessary.

 

Section 4.8

 

Complete section updated

 

Section 5.1

 

ATC Code is no longer pending.

 

Microbiology section changed from:

 

Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Coccidioides immitis, Fonsecaea pedrosoi, and species of Fusarium.

 

To:

 

Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus. The microbiological data suggest that posaconazole is active against Rhizomucor, Mucor, and Rhizopus, however the clinical data are currently too limited to assess the efficacy of posaconazole against these causative agents.

 

Pharmacokinetic/Pharmacodynamic Relationships changed from:

 

A correlation between total drug exposure divided by MIC (AUC/MIC) and clinical outcome was observed.

 

To:

 

A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical outcome was observed.

 

Table 2 has become table 3

 

New sections added re: Treatment of azole-susceptible Oropharyngeal Candidiasis (OPC), Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899) and Use in paediatric patients.

 

Section 5.2

 

First paragraph, 1st sentence changed from:

 

Posaconazole is absorbed with a median tmax of ~ 5 hours.

 

To:

 

Posaconazole is absorbed with a median tmax of 3 hours (fed patients).

 

Fifth paragraph – the word “drug” changed to “compound”

 

Sixth paragraph changed from:

 

Pharmacokinetics in Special Populations

Children (< 18 years)

Following administration of 800 mg per day of posaconazole as a divided dose, mean trough plasma concentrations from 12 patients 8 - 17 years of age (776 ng/ml) were similar to concentrations from 194 patients 18 - 64 years of age (817 ng/ml). No pharmacokinetic data are available from paediatric patients less than 8 years of age.

 

To:

 

Pharmacokinetics in Special Populations

Children (< 18 years)

Following administration of 800 mg per day of posaconazole as a divided dose for treatment of invasive fungal infections, mean trough plasma concentrations from 12 patients 8 - 17 years of age (776 ng/ml) were similar to concentrations from 194 patients 18 - 64 years of age (817 ng/ml). No pharmacokinetic data are available from paediatric patients less than 8 years of age.  Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was comparable among ten adolescents (13-17 years of age) to Cav achieved in adults (> 18 years of age).

 

Seventh paragraph changed from:

Gender

Results from a multiple dose study in healthy volunteers (12 per gender) and data from patients in the pivotal efficacy study (79 females and 152 males) indicate that gender does not affect posaconazole pharmacokinetics.

 

To:

Gender

The pharmacokinetics of posaconazole are comparable in men and women.

 

Eighth paragraph changed from:

 

Elderly (³ 65 years)

An increase in Cmax (26 %) and AUC (29 %) was observed in elderly subjects (24 subjects ³ 65 years of age) relative to younger subjects (24 subjects 18 - 45 years of age). However, the safety profile of posaconazole between the young and elderly patients was similar. Therefore, no dose adjustment is required for age.

 

To:

Elderly (³ 65 years)

An increase in Cmax (26 %) and AUC (29 %) was observed in elderly subjects (24 subjects ³ 65 years of age) relative to younger subjects (24 subjects 18 - 45 years of age). However, in clinical efficacy trials, the safety profile of posaconazole between the young and elderly patients was similar.

 

Ninth paragraph, the last sentence “Therefore no dose adjustment is recommended” has been deleted.

 

Section 10 – updated date of revision of text.

 

 

Reasons for adding or updating:

  • New SPC for new product