4.5 Interaction with other medicinal products and other forms of interaction

CYP450 inhibitors and inducers

Zolpidem is metabolised by some enzymes of the cytochrome P450-family.  The main enzyme is CYP3A4, but CYP1A2 is involved as well. Since CYP3A4 plays an important role in zolpidem tartrate metabolism, possible interactions with drugs that are substrates or inducers of CYP3A4 should be considered. CYP3A4 inducers, such as rifampicin and St John’s wort can reduce the plasma concentration and therefore effect (see below).

 

Co-administration of ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.

 

Co-administration of fluvoxamine may increase blood levels of zolpidem, concurrent use is not recommended.

 

Rifampicin (a CYP3A4 inducer) induces the metabolism of zolpidem, resulting in approximately 60% reduction in peak plasma concentrations and possibly decreased efficacy.  Similar effects might be expected also with other strong inducers of cytochrome P450-enzymes. However when zolpidem tartrate was administered with itraconazole (a CYP3A4 inhibitor) its pharmacokinetics and pharmacodynamics were not significantly modified. The clinical relevance of these results is unknown.

 

Co-administration of zolpidem with ketoconazole (200mg twice daily), a potent CYP3A4 inhibitor, prolonged zolpidem elimination half-life, increased total AUC, and decreased apparent oral clearance when compared to zolpidem plus placebo. The total AUC for zolpidem, when co-administered with ketoconazole, increased by a factor of 1.83 when compared to zolpidem alone. A routine dosage adjustment of zolpidem is not considered necessary, but patients, should be advised that use of zolpidem with ketoconazole may enhance the sedative effects.

 

Maximum plasma concentration and AUC has been shown to decrease when zolpidem was administered with St John’s wort compared to zolpidem alone. Coadministration with St John’s wort can lower levels of zolpidem in the blood and is therefore not recommended.

10. DATE OF REVISION OF THE TEXT

November 2016April 2017

4.8 Undesirable effects

SOC	Frequency
	Common	Uncommon	Rare	Not known
Infections and infestations	Upper respiratory tract infection, lower respiratory tract infection
Immune system disorders				Angioneurotic oedema
Psychiatric disorders	Hallucination, agitation, nightmare, numbed emotions	Irritability, confusion		Restlessness, aggression, delusion, anger, psychosis, abnormal behaviour, sleep walking (see section 4.4), dependence (withdrawal symptoms, or rebound effects may occur after treatment discontinuation), depression, decreased libido
Nervous system disorders	Somnolence, headache, dizziness, increased insomnia, cognitive disorders such as anterograde amnesia: (amnestic effects may be associated with inappropriate behaviour), drowsiness during the following day, reduced alertness	Ataxia		Depressed level of consciousness
Eye disorders		Double vision
Ear and labyrinth disorders	Vertigo
Respiratory, thoracic and mediastinal disorders				Respiratory depression (see section 4.4)
Gastrointestinal disorders	Diarrhoea, nausea, vomiting, abdominal pain
Hepatobiliary disorders				Elevated liver enzymes, hepatocellular, cholestatic or mixed liver injury
Skin and subcutaneous tissue disorders	Skin reactions			Rash, pruritus, urticaria, hyperhidrosis
Musculoskeletal and connective tissue disorders	Back pain			Muscle weakness
General disorders and administration site conditions	Fatigue		Paradoxical reactions	Gait disturbance, drug tolerance, falls (predominantly in elderly patients and when zolpidem was not taken in accordance with prescribing recommendation)

4.4 Special warnings and precautions for use

Following section added:
Serious injuries
Because of its pharmacological properties, zolpidem can cause drowsiness and reduced levels of awareness, which can lead to falls and thereby serious injury.

4.5 Interaction with other medicinal products and other forms of interaction

(muscle relaxant added):
Combination with CNS depressants:
Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives/muscle relaxant, antidepressant agents, narcotic analgesics, antiepileptic drugs, anaesthetics and sedative antihistamines. 

(CYP3A4 added):
CYP450 inhibitors and inducers:
Zolpidem is metabolised by some enzymes of the cytochrome P450-family.  The main enzyme is CYP3A4, but CYP1A2 is involved as well. Since CYP3A4 plays an important role in zolpidem tartrate metabolism, possible interactions with drugs that are substrates or inducers of CYP3A4 should be considered.
Co-administration of ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.
Co-administration of fluvoxamine may increase blood levels of zolpidem, concurrent use is not recommended.

(Interaction with selective serotonin reuptake inhibitors added, no interaction with warfarin, haloperidol, chlorpromazine, itraconazole or digoxin):
Other drugs:
Caution should be observed when other psychoactive drugs are used.
No clinical significant pharmacokinetic interactions have been shown with selective serotonin reuptake inhibitors (fluoxetine and sertraline).
When zolpidem tartrate was administered with ranitidine, no significant pharmacokinetic interactions were observed.
Zolpidem does not interact with warfarin, haloperidol, chlorpromazine, itraconazole or digoxin.

4.6 Fertility, pregnancy and lactation

(breast-feeding statement updated):
Breast-feeding
There are insufficient data to evaluate the safety of using zolpidem while breast-feeding. Zolpidem passes into breast milk in small amounts. Zolpidem should therefore not be used by breast-feeding mothers since effects on the infant are not studied.

4.8 Undesirable effects

Back pain added as Common side effect under Musculoskeletal and connective tissue disorders

10. Date of revision of the text

Revision date changed to May 2015



(internal reference: SE/H/0310/IB/047 PR 507966)

4.1 - Insomnia in adults added

4.2 - Adulst dosage changed to

The treatment should be taken in a single intake and not be re-administered during the same night.

The recommended daily dose for adults is 10 mg to be taken immediately at bedtime. The lowest effective daily dose of zolpidem should be used and must not exceed 10 mg.

Text Added

The available evidence from placebo-controlled clinical trials is presented in section 5.1.

4.4 - Text added

Next-day psychomotor impairment
The risk of next-day psychomotor impairment, including impaired driving ability, is increased if:
• zolpidem is taken within less than 8 hours before performing activities that require mental alertness (see section 4.7);
• a dose higher than the recommended dose is taken;
• zolpidem is co-administered with other CNS depressants or with other drugs that increase the blood levels of zolpidem, or with alcohol or illicit drugs (see section 4.5).

Zolpidem should be taken in a single intake immediately at bedtime and not be re-administered during the same night.


4.5 Text added

concomitant use of zolpidem with these drugs may increase drowsiness and next-day psychomotor impairment, including impaired driving ability (see section 4.4 and 4.7). Also, isolated cases of visual hallucinations were reported in patients taking zolpidem with antidepressants including bupropion, desipramine, fluoxetine, sertraline and venlafaxine.

Co-administration of fluvoxamine may increase blood levels of zolpidem, concurrent use is not recommended.

CYP450 inhibitors and inducers: Co-administration ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.


4.7 - 'Effects on ability to drive and use machines' changed to

Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision and reduced alertness and impaired driving the morning after therapy (see section 4.8). In order to minimise this risk a resting period of at least 8 hours is recommended between taking zolpidem and driving, using machinery and working at heights.

Driving ability impairment and behaviours such as ‘sleep-driving’ have occurred with zolpidem alone at therapeutic doses.

Furthermore, the co-administration of zolpidem with alcohol and other CNS depressants increases the risk of such behaviours (see section 4.4 and 4.5). Patients should be warned not to use alcohol or other psychoactive substances when taking zolpidem.


4.8 Reporting of side effect updated according to new HPRA guidelines

5.1 Text added

The randomised trials only showed convincing evidence of efficacy of 10 mg zolpidem.

In a randomised double-blind trial in 462 non-elderly healthy volunteers with transient insomnia, zolpidem 10 mg decreased the mean time to fall asleep by 10 minutes compared to placebo, while for 5 mg zolpidem this was 3 minutes.

In a randomised double-blind trial in 114 non-elderly patients with chronic insomnia, zolpidem 10 mg decreased the mean time to fall asleep by 30 minutes compared to placebo, while for 5 mg zolpidem this was 15 minutes.

In some patients, a lower dose of 5 mg could be effective.

Paediatric population: Safety and efficacy of zolpidem have not been established in children aged less than 18 years. A randomised placebo-controlled study in 201 children aged 6-17 years with insomnia associated with Attention Deficit Hyperactivity Disorder (ADHD) failed to demonstrate efficacy of zolpidem 0.25 mg/kg/day (with a maximum of 10 mg/day) as compared to placebo. Psychiatric and nervous system disorders comprised the most frequent treatment emergent adverse events observed with zolpidem versus placebo and included dizziness (23.5% versus 1.5%), headache (12.5% versus 9.2%), and hallucinations (7.4% versus 0%) (see section 4.2).

In section 1 - caps lock removed on film-coated
In section 2 - wording changed on how excipients per tablet are mentioned
In section 3 - halves changed to doses
In section 4.2 - Information regarding paediattric population added - Safety and effectiveness of zolpidem in paediatric patients under the age of 18 years have not been established. Therefore, children and adolescents under 18 years of age should not be treated with Zolpidem

In section 4.3 - excipients linked to the section 6.1
In section 4.4 - Psychic changed to psychological, Text added regarding safety and effectiveness of zolpidem.
In section 4.5 - Text relating to Interaction with Sertraline added. Text relating to CYP3A4 inducers and inhibitors changed
In section 4.6 - Title changed to include Fertility, mention of severe neonatal respiratory depression added
In section 4.8 - Gastrointestinal events added are included in CNS reactions for evidence of dose connection for reactions. Changes made to table, please refer to SPC. Psychic changed to Psychological. reposrting of adverse events changed
In section 4.9 - Text added in relation to elimination of flumazenil.
In section 5.1 - ATC code- correction - O changed to 0
In section 6.1 - the excipients are listed in capslocks
In section 6.6 - 'and other handling' removed from title
In section 10 - date of revision changed to June 2014

4.2 Posology and method of administration

In certain cases extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient’s status

As with all hypnotics, long-term use is not recommended and a course of treatment should not exceed four weeks. In certain cases extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient ‘s status.

The product acts rapidly and therefore should be taken with fluid just before going to bed, or in bed.

Adults

The recommended daily dose for adults is 10 mg.

 

Elderly (over 65 years) or debilitated patients

Elderly or debilitated patients may be especially sensitive to the effects of Zolpidem therefore a 5 mg dose is recommended. These recommended doses should not be exceeded.

 

Hepatic impairment

Patients with hepatic insufficiency do not clear the drug as rapidly as normal individuals; therefore dosage should begin at 5 mg in these patients with particular caution being exercised in elderly patients. In adults (under 65 years) dosage may be increased to 10 mg only where the clinical response is inadequate and the drug is well tolerated.
Dosage
The recommended daily dose for adults is 10 mg zoplidem tartrate immediately before going to bed. In elderly or debilitated patients who may be especially sensitive to the effects of zolpidem and in patients with hepatic insufficiency who do not clear the active substance as rapidly as normal individuals, a dose of 5 mg zolpidem tartrate is recommended. This dose should only be increased to 10 mg zolpidem tartrate where the clinical response is inadequate and the medicinal product is well tolerated. The total dose of zolpidem tartrate should not exceed 10 mg in any patient.
Children and adolescents under 18 years of age should not be treated with Zolpidem.

The total dose of Zolpidem should not exceed 10mg in any patients.

 

Children and adolescents

Children and adolescents under 18 years of age should not be treated with Zolpidem.

4.3 Contraindications

Acute and/or severe respiratory insufficiency.

4.4 Special warnings and precautions for use

Dependence

Use of benzodiazepines or benzodiazapine-like agents may lead to the development of physical and psychic dependence of these products. The risk of dependence increases with dose and duration of treatment and is also greater in patients with a history of alcohol or drug abuse.
These patients should be under careful surveillance when receiving hypnotics.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches or muscle pain, extreme anxiety and tension, restlessness, confusion, irritability and insomnia. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

 

Psychiatric and “paradoxical” reactions

When using benzodiazepines or benzodiazepine-like agents, reactions like restlessness, and increased insomnia may occur.  Also agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, somnambulism and other nightly unconscious behaviours, like eating and car driving, inappropriate behaviour, increased insomnia and other adverse behavioural effects are known to occur. Should this occur, use of the product should be discontinued. These reactions are more likely to occur in the elderly.

Somnambulism and associated behaviours

Sleep walking and other associated behaviours such as “sleep driving”, preparing and eating food, making phone calls or having sex, with amnesia for the event, have been reported in patients who had taken zolpidem and were not fully awake. The use of alcohol and other CNS-depressants with zolpidem appears to increase the risk of such behaviours, as does the use of zolpidem at doses exceeding the maximum recommended dose. Discontinuation of zolpidem should be strongly considered for patients who report such behaviours (see section 4.5 and section 4.8).

Depression

Benzodiazepine and benzodiazepine-like agents should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients). Use in depression Zolpidem should be administered with caution in patients exhibiting symptoms of depression.  Suicidal tendencies may be present.  Due to the possibility of intentional overdose by the patient, the lowest amount of the drug that is feasible should be supplied to these patients. Pre-existing depression may be unmasked during use of zolpidem. Since insomnia may be a symptom of depression, the patient should be re-evaluated if insomnia persists.

Benzodiazepine and benzodiazepine-like agents should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).


4.5 Interaction with other medicinal products and other forms of interaction

Caution should be observed when other psychoactive drugs are used.

 

No clinical significant pharmacokinetic or pharmacodynamic interactions with selective serotonine reuptake inhibitors (fluoxetin and sertraline) have been described.

 

Zolpidem is metabolised by some enzymes of the cytochrome P450-family. The main enzyme is CYP3A4, but CYP1A2 is involved as well

Compounds that inhibit hepatic enzymes (particularly CYP3A4) may increase plasma concentrations and enhance the activity of zolpidem.  However, when zolpidem is administered with ketokonazol (200 mg twice daily) a potent CYP3A4 inhibitor, the AUC increases with 83%. It is not necessary to adjust the dose of zolpidem by routine but the patient should be informed that use of zolpidem together with ketokonazol may increase the sedative effect. Itraconazol (CYP3A4 inhibitor), the pharmacokinetic and pharmacodynamic effects are not significantly different.  The clinical relevance of these results is unknown

Others: when zolpidem tartrate was administered with ranitidine or cimetidine, no significant pharmacokinetic interactions were observed.

4.6 Pregnancy and lactation
Minor text change

4.8 Undesirable effects

There is evidence for a dose connection for reactions associated with use of zolpidem, especially certain CNS-reactions. Theoretically they should be less if zolpidem is taken immediately before bedtime. They occur most frequently in elderly patients.

SOC	Frequency
	Common	Uncommon	Rare	Not known
Immune system disorders				Angioneurotic disorders
Psychiatric disorders	Hallucination, agitation, nightmare Numbed emotions, confusion	Irritability	Decreased libido	Restlessness, aggression, delusion, anger, psychosis, abnormal behaviour, sleep walking (see section 4.4), dependence (withdrawal symptoms, or rebound effects may occur after treatment discontinuation), depression dependence
Nervous System Disorders	Somnolence, headache, dizziness, increased insomnia, anterograde amnesia: (amnestic effects may be associated with inappropriate behaviour) drowsiness during the following day,headache, dizziness, reduced alertness, amnesia	Ataxia		Depressed level of consciousness
Eye disorders	Double vision
Ear and labyrinth disorders	Vertigo
Gastrointestinal disorders	Diarrhoea, nausea, vomiting, abdominal pain
Hepatobililary disorders				Elevated liver enzymes
Skin and Subcutaneous tissue disorders	Skin reactions			Rash, pruritus, urticaria, hyperhidrosis
Musculoskeletal, connective tissue and bone disorders		Muscle weakness
General Disorders	Fatigue	Fatigue	Paradoxical reactions	Gait disturbance, drug tolerance, fall (predominantly in elderly patients and when zolpidem was not taken in accordance with prescribing recommendation)

Psychiatric and “paradoxical” reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusions, rage, nightmares, increased insomnia, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects may occur when using benzodiazepines and benzodiazepine-like agents. Such reactions are more likely to occur in the elderly (see section 4.4).

4.9 Overdose

In reports of overdose with zolpidem alone or with other CNS-depressant agents (including alcohol), impairment of consciousness has ranged from somnolence to light coma and fatal outcomes have been reported

Use of flumazenil may be considered when serious symptoms are observed. Flumazenil administration may contribute to the appearance of neurological symptoms (convulsions).

Section 9: 30/06/2003 added as Date of First Authorisation.