Zolpidem

Registered South African indications: 

• Short-term treatment of insomnia

Contraindications

South African recommendations

Oral (fct, tab)

• Hypersensitivity to the active ingredient or any of its excipients
• Myasthenia gravis
• Sleep apnoea syndrome
• Acute and severe pulmonary insufficiency, as respiratory failure may be precipitated
• Severe hepatic insufficiency
• Children under the age of 18
• Coadministration with HIV protease inhibitors such as ritonavir

Oral (MR tab)

• Hypersensitivity to the active ingredient or any of its excipients
• Children under the age of 18 years
• Sleep apnoea syndrome
• Myasthenia gravis
• Severe hepatic impairment
• Acute and/or severe respiratory impairment
• Pregnancy
• Lactation

Recommendations in other jurisdictions

• Hypersensitivity to zolpidem tartrate or any of the excipients
• Obstructive sleep apnoea
• Myasthenia gravis
• Severe hepatic insufficiency
• Acute and/or severe respiratory depression
• Zolpidem should not be prescribed for children
• Zolpidem should not be prescribed to patients with psychotic illness

Cautions 

• Pregnancy (fct, tab) (South African recommendations)
• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (fct, tab) (South African recommendations)
• Breastfeeding (Recommendations in other jurisdictions)
• Mild to moderate hepatic impairment
• Elderly
• Failure of insomnia to remit after 7-14 days of use
• Respiratory insufficiency
• History of alcohol, substance abuse or dependence
• Depression
• Treatment >4 weeks
• Abrupt withdrawal
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct, tab, modified release tablet (MR tab)

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Short-term treatment of insomnia
- When the disorder is severe, disabling or subjecting the individual to extreme distress

• Oral (fct, tab): 10mg, dly at night; Treatment duration: A few days to 2 weeks; Max: 10mg/24hrs; Max duration: 4 weeks, including the tapering off process
• Oral (MR tab): 12.5mg, dly at night; Treatment duration: 4-14 days; Max: 12.5mg/24hrs; Max duration: 4 weeks, including the tapering off process

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Treatment should be as short as possible and should not exceed four weeks, including the period of tapering off. Extension beyond the maximum treatment period should not take place without re-evaluation of the patient's status, since the risk of abuse and dependence increases with the duration of treatment

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 Zolpidem should be taken immediately before going to bed, or in bed

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For faster sleep onset, the medication should not be administered with or immediately after a meal. Tablets should not be halved, crushed, or chewed. The medication should be taken in a single intake and not be readministered during the same night (MR tab)

Contraindicated

Pregnancy

South African recommendations

Oral (fct, tab)

• Caution; positive evidence of risk
• Safety in pregnancy has not been established. If zolpidem is administered during the late phase of pregnancy, or during labour, effects on the neonate such as hypothermia, hypotonia and moderate respiratory depression, can be expected due to the pharmacological action of the product
• Infants born to mothers who take zolpidem chronically during the latter stages of pregnancy may develop physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period

Oral (MR tab)

• Contraindicated
• Safety in pregnancy has not been established
• The use of zolpidem during pregnancy should be avoided. If zolpidem is prescribed to a woman of childbearing potential, she should be warned to contact her medical practitioner about stopping zolpidem if she intends to become, or suspects that she is pregnant
• If for compelling medical reasons zolpidem is administered during the late phase of pregnancy or during labour, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected due to the pharmacological action of zolpidem
• Infants born to mothers who took hypnotics, including zolpidem, chronically during the latter stages of pregnancy may have developed physical dependence and may be at risk of developing withdrawal symptoms in the postnatal period

Recommendations in other jurisdictions

• Caution; not recommended
• Zolpidem crosses the placenta. A large amount of data collected from cohort studies has not demonstrated evidence of the occurrence of malformations following exposure to benzodiazepines during the first trimester of pregnancy. However, in certain epidemiological case-control studies, an increased incidence of cleft lip and palate was observed with benzodiazepines
• Cases of reduced foetal movement and foetal heart rate variability have been described after administration of benzodiazepines during the second and/ or third trimester of pregnancy. Administration of zolpidem during the late phase of pregnancy, or during labour has been associated with effects on the neonate, such as hypothermia, hypotonia, feeding difficulties (which may result in poor weight gain), and respiratory depression, sometimes severe, due to the pharmacological action of the product
• Moreover, infants born to mothers who took sedative/ hypnotic agents chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended
• If zolpidem is prescribed to a woman of childbearing potential, she should be warned to contact her physician about stopping the product if she intends to become or suspects that she is pregnant

Breastfeeding

South African recommendations

Oral (fct, tab)

• Caution; not recommended
• Zolpidem should not be administered to breast-feeding mothers. Small quantities of zolpidem appear in breast milk

Oral (MR tab)

• Contraindicated
• As zolpidem is excreted in breast milk, it's use in breastfeeding mothers is not recommended

Recommendations in other jurisdictions

• Caution; not recommended
• Small quantities of zolpidem appear in breast milk. The use of zolpidem in nursing mothers is therefore not recommended

Renal Impairment

• No dose adjustment recommended

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended (tab) 
  Oral (tab): Initial: 5mg, dly at night
  Increase to 10mg where clinical response is inadequate and the medicine is well tolerated
• Mild to moderate: Caution; no information available (MR tab)
• Severe: Contraindicated

Elderly

• Caution; dose adjustment recommended 
  Oral (tab): 5mg, dly at night
  Oral (MR tab): Use not recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Diarrhoea, nausea, vomiting, abdominal pain and fatigue are very common side effects of zolpidem that may potentially be porphyrinogenic if leading to a decrease in carbohydrate intake 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Hallucination
• Agitation
• Nightmare
• Depression
• Confusional state
• Irritability
• Restlessness
• Aggression
• Euphoric mood
• Delusion
• Anger  
• Psychosis
• Abnormal behaviour
• Somnambulism
• Dependence
• Libido disorder
• Somnolence
• Headache
• Dizziness
• Exacerbated insomnia
• Cognitive disorders
• Anterograde amnesia
• Paraesthesia
• Tremor
• Disturbance in attention
• Speech disorder
• Depressed level of consciousness
• Fatigue
• Gait disturbance
• Drug tolerance

Respiratory Disorders

• Respiratory depression
• Upper respiratory tract infections
• Lower respiratory tract infections

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain

Hepatobiliary Disorders

• Elevated hepatic enzymes
• Hepatocellular, cholestatic or mixed hepatic injury

Endocrine and Metabolic Disorders

• Appetite disorder

Musculoskeletal Disorders

• Back pain
• Myalgia
• Muscle spasms
• Muscular weakness

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Urticaria
• Hyperhidrosis

Immune, Blood and Lymphatic System Disorders

• Angioneurotic oedema

Sensory Disorders

• Diplopia
• Blurred vision
• Visual impairment

Others

• Falls

• HIV protease inhibitors
• Ritonavir
• Central nervous system depressants
• Antipsychotics (neuroleptics)
• Hypnotics
• Anxiolytics/ sedatives
• Antidepressant agents
• Bupropion
• Desipramine
• Fluoxetine
• Sertraline
• Venlafaxine
• Fluvoxamine
• Narcotic analgesics
• Antiepileptic agents
• Anaesthetics
• Sedative antihistamines
• Ciprofloxacin
• CYP450 inhibitors
• CYP450 inducers
• Itraconazole
• Ketoconazole
• CYP3A4 inducers
• Rifampicin

Other interactions

• Alcohol
• St John's Wort

None routine. Some cases may require

• Respiratory function

Considerations for use

• The cause of insomnia should be identified wherever possible and the underlying factors treated before a hypnotic is prescribed
• The failure of insomnia to remit after a 7 – 14 day course of treatment may indicate the presence of a primary psychiatric or physical disorder, and the patient should be carefully re-evaluated at regular intervals

Next-day psychomotor impairment

• Like other sedative/ hypnotic drugs, zolpidem has CNS depressant effects. 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
  - 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

Dependence

• Use of zolpidem may lead to the development of abuse and/or physical and psychological dependence. The risk of dependence increases with dose and duration of treatment
• Cases of dependence have been reported more frequently in patients treated with zolpidem for longer than 4 weeks
• The risk of abuse and dependence is also greater in patients with a history of psychiatric disorders and/or alcohol or substance or drug abuse or dependence. Zolpidem should be used with extreme caution in patients with current or a history of alcohol, substance or drug abuse, or dependence
• 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 and irritability
• In severe cases, the following symptoms may occur: derealisation, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures

Tolerance

• Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines and benzodiazepine-like agents like zolpidem may develop after repeated use for a few weeks

Zolpidem, an imidazopyridine, selectively binds to the omega-1 receptor subtype (also known as the benzodiazepine-1 subtype) which is the alpha unit of the GABA-A receptor complex. The modulation of the chloride anion channel via this receptor leads to the specific sedative effects demonstrated by zolpidem.

Tablet 5mg

• Medploz (Aurobindo)

Tablet 10mg

• Adco-Zolpidem (Adcock Ingram)
• Ivedal (Sanofi Aventis) originator
• Medploz (Aurobindo)
• Mylan zolpidem (Mylan)
• Noxidem (Sandoz)
• Nyxe (Novagen)
• Stilnox (Sanofi) originator
• Zizz 10 (Trinity Pharma)
• Zolnoxs (Pharmacare)
• Zolpihexal (Sandoz)

Tablet 12.5mg

• Stilnox MR (Sanofi) originator