Last Updated on eMC 11-02-2015 View medicine  | Roche Products 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 2 - Qualitative and quantitative composition
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:22-01-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



2        QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Active ingredient: midazolam as hydrochloride.

Ampoules 10mg/2ml; for i.v., i.m. and rectal administration.

For a full list of excipients, see section 6.1.



4.8       Undesirable effects

 

The following undesirable effects have been reported (frequency not known, cannot be estimated from the available data) to occur when midazolam is injected:

 

Frequency categories are as follows:

Very common: ³1/10;             

Common ³1/100 to <1/10;

Uncommon ³1/1,000 to <1/100

Rare (³1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

 

Immune System Disorders

 

frequency not known

Hypersensitivity, angioedema, anaphylactic shock

 

Psychiatric Disorders

 

frequency not known

Confusional state, euphoric mood, hallucinations

 

Agitation*,  hostility*, rage*, aggressiveness*, excitement*

 

Physical drug dependence and withdrawal syndrome

 

Abuse


[....]

 

*Such paradoxical drug reactions have been reported, particularly among children and the elderly (see section 4.4)

**Anterograde amnesia may still be present at the end of the procedure and in few cases prolonged amnesia has been reported (see section 4.4).

***There have been reports of falls and fractures in benzodiazepine users. The risk of falls and fractures is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

Dependence: Use of midazolam - even in therapeutic doses - may lead to the development of physical dependence. After prolonged i.v. administration, discontinuation, especially abrupt discontinuation of the product, may be accompanied by withdrawal symptoms including withdrawal convulsions (see section 4.4). Cases of abuse have been reported.

Severe cardiorespiratory adverse events have occurred. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered (see section 4.4).

            Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.



10      DATE OF REVISION OF THE TEXT

 

30Th January 2014. 22nd January 2015

 

Hypnovel is a registered trade mark.

 




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:30-01-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text = new text

Strike through text = deleted text

 

4.8       Undesirable effects

 

[…]

 

[…]

 

Injury, Poisoning and Procedural Complications

 

 

frequency not known

Falls, fractures***

[…]

 

 

*Such paradoxical drug reactions have been reported, particularly among children and the elderly (see section 4.4)

**Anterograde amnesia may still be present at the end of the procedure and in few cases prolonged amnesia has been reported (see section 4.4).

***There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

 

[…]

10      DATE OF REVISION OF THE TEXT

April 2012 30 January 2014

Reasons for adding or updating:

  • 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
  • Change to section 4.4 - Special warnings and precautions for Use

Date of revision of text on the SPC:30-04-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underlined text = new text
Struck through text = deleted text

4.4       Special warnings and precautions for use

[…]

This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e essentially ‘sodium free’.

 

4.5       Interaction with other medicinal products and other forms of interaction

Pharmacokinetic Interactions

Midazolam is metabolised by CYP3A4. Inhibitors and inducers of CYP3A4 have the potential to respectively increase and decrease the plasma concentrations and, subsequently, the effects of midazolam thus requiring dose adjustments accordingly. Pharmacokinetic interactions with CYP3A4 inhibitors or inducers are more pronounced for oral as compared to i.v. midazolam, in particular since CYP3A4 also exists in the upper gastro-intestinal tract. This is because for the oral route both systemic clearance and availability will be altered while for the parenteral route only the change in the systemic clearance becomes effective. After a single dose of i.v. midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. However, after prolonged dosing of midazolam, both the magnitude and duration of effect will be increased in the presence of CYP3A4 inhibition.

 

There are no available studies on CYP3A4 modulation on the pharmacokinetics of midazolam after rectal and intramuscular administration.It is expected that these interactions will be less pronounced for the rectal than for the oral route because the gastro-intestinal tract is by-passed whereas after i.m. administration the effects of CYP3A4 modulation should not substantially differ from those seen with i.v. midazolam.

 

[…]

 

Drugs that inhibit CYP3A4

Azole antifungals

·           Ketoconazole increased the plasma concentrations of intravenous midazolam by 5-fold while the terminal half-life increased by about 3-fold. If parenteral midazolam is co-administered with the strong CYP3A4 inhibitor ketoconazole, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Staggered dosing and dosage adjustment should be considered, especially if more than a single i.v. dose of midazolam is administered. The same recommendation may apply also for other azole antifungals (see further), since increased sedative effects of i.v. midazolam, although lesser, are reported.

[…]

Drugs that induce CYP3A4

[…]

4.8       Undesirable effects

The following undesirable effects have been reported (very rarelyfrequency not known, cannot be estimated from the available data) to occur when midazolam is injected:

Immune System Disorders: Generalised hypersensitivity

Frequency categories are as follows:

Very common: ³1/10;             

Common ³1/100 to <1/10;

Uncommon ³1/1,000 to <1/100

Rare (³1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

 

Immune System Disorders

 

frequency not known

Hypersensitivity, anaphylactic shock

 

Psychiatric Disorders

 

frequency not known

Confusional state, euphoric mood, hallucinations

 

Agitation*,  hostility*, rage*, aggressiveness*, excitement*

 

Physical drug dependence and withdrawal syndrome

Nervous System Disorders

 

frequency not known

Involuntary movements (including tonic/clonic movements and muscle tremor)*, hyperactivity*

 Sedation (prolonged and postoperative), alertness decreased, somnolence, headache, dizziness, ataxia,  anterograde amnesia**, the duration of which is directly related to the administered dose

Convulsions have been reported in premature infants and neonates

Drug withdrawal convulsions

Cardiac Disorders

 

frequency not known

Cardiac arrest, bradycardia

Vascular Disorders

 

frequency not known

Hypotension, vasodilation, thrombophlebitis, thrombosis

Respiratory Disorders

 

frequency not known

Respiratory depression, apnoea, respiratory arrest, dyspnea, laryngospasm, hiccups

Gastrointestinal Disorders

 

frequency not known

Nausea, vomiting, constipation, dry mouth

Skin and Subcutaneous Tissue Disorders

 

frequency not known

Rash, urticaria, pruritus

General Disorders and Administration Site Conditions

 

 

frequency not known

Fatigue, injection site erythema, injection site pain

Injury, Poisoning and Procedural Complications

 

 

frequency not known

Falls, fractures

Social Circumstances

 

frequency not known

Assault*

 

*Such paradoxical drug reactions (skin reactions, cardiovascular reactions, bronchospasm), anaphylactic shock.

Psychiatric Disorders: Confusional state, euphoric mood, hallucinations.

Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reported, particularly among children and the elderly (see section 4.4)

**Anterograde amnesia may still be present at the end of the procedure and in few cases prolonged amnesia has been reported (see section 4.4).

Dependence: Use of midazolam - even in therapeutic doses - may lead to the development of physical dependence. After prolonged i.v. administration, discontinuation, especially abrupt discontinuation of the product, may be accompanied by withdrawal symptoms including withdrawal convulsions (see section 4.4).

Nervous System Disorders: Prolonged sedation, decreased alertness, somnolence, headache, dizziness, ataxia, postoperative sedation, anterograde amnesia, the duration of which is directly related to the administered dose. Anterograde amnesia may still be present at the end of the procedure and in isolated cases prolonged amnesia has been reported.

Convulsions have been reported in premature infants and neonates.

Cardiac Disorders: Severe cardiorespiratory adverse events have occurred. These have included cardiac arrest, hypotension, bradycardia, vasodilating effects. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered (see section 4.4).

Respiratory Disorders: Severe cardiorespiratory adverse events including respiratory depression, apnoea, respiratory arrest, dyspnoea, laryngospasm have been reported. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered (see section 4.4). Hiccup.

Gastrointestinal System Disorders: Nausea, vomiting, constipation, dry mouth.

Skin and Appendages Disorders: Skin rash urticaria, pruritus.

General and Application Site Disorders: Fatigue, erythema and pain on injection site, thrombophlebitis, thrombosis.

Injury, Poisoning and Procedural Complications: An increased risk for falls and fractures has been recorded in elderly benzodiazepine users.

10      DATE OF REVISION OF THE TEXT

 26 March 2010April 2012

Reasons for adding or updating:

  • Change to section 1 -Name of the Medicinal product

Date of revision of text on the SPC:26-03-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike through deleted:

 

1        NAME OF THE MEDICINAL PRODUCT

Hypnovel Ampoules 10mg/2ml solution for injection

 

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 4.9 - Overdose

Date of revision of text on the SPC:01-02-2008

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Due to extensive changes to this SPC, please copy and paste the following url into your web browser to view the change details:
 

Reasons for adding or updating:

  • Change to section 6. 4 - Special Precautions for Storage

Reasons for adding or updating:

  • Change to section 1 - trade name
  • Change to section 2 - qualitative and quantitative composition
  • Change to section 3 - pharmaceutical form
  • Change to section 4.1 - Therapeutic Indications
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.3 - Contra-indications
  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.5 - Interactions with other Medicaments 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 - Pharmacological Properties

Reasons for adding or updating:

  • Transferred from eMC version 1

Reasons for adding or updating:

  • No reasons supplied

Reasons for adding or updating:

  • No reasons supplied