SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zolpidem tartrate 10 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg zolpidem tartrate equivalent to 8.04 mg zolpidem.

Excipient: Each 10 mg film-coated tablet contains 83.2 mg lactose (as lactose monohydrate)

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

White to off-white, oval shaped, biconvex, film-coated tablets debossed with ‘E’ on one side and ‘80’ with a score line between ‘8’ and ‘0’ on other side. The tablet can be divided into equal halves.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For short-term treatment of insomnia.

Benzodiazepines or benzodiazepine-like medicinal products should only be used in insomnia of clinically relevant severity when the disorder is disabling or subjecting the individual to extreme distress.

4.2 Posology and method of administration

For oral use

The medicinal product should be taken with fluid just before going to bed.

The duration of treatment should be as short as possible. In general it should be a few days to two weeks with a maximum, including the tapering off process, of four weeks.

The tapering off process should be tailored to the individual.

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.

Adults:

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.

Elderly:

In elderly or debilitated patients who may be especially sensitive to the effects of zolpidem tartrate a dose of 5 mg is recommended. This dose should only be increased to 10 mg where the clinical response is inadequate and the medicinal product is well tolerated.

Patients with hepatic impairment

Patients with hepatic impairment who do not clear the medicinal product as rapidly as normal individuals, a dose of 5 mg is recommended. This dose should only be increased to 10 mg 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

Children and adolescents of less than 18 years of age must not be treated with Zolpidem tartrate.

4.3 Contraindications

•    Hypersensitivity to zolpidem tartrate or to any of the excipients

•    Myasthenia gravis

•    Severe respiratory depression

•    Obstructive sleep apnoea

•    Severe hepatic insufficiency

•    Children and adolescents of less than 18 years of age

4.4 Special warnings and precautions for use

General

The cause of insomnia should be identified wherever possible. The underlying factors should be 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, which should be evaluated.

General information relating to effects seen following administration of benzodiazepines or other hypnotic agents which should be taken into account by the prescribing physician are described below.

Tolerance

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

Dependence

Use of benzodiazepines or benzodiazepine-like agents may lead to the development of physical and psychological 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 psychiatric disorders and/or alcohol or medicinal product abuse.

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, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

Rebound insomnia

A transient syndrome whereby the symptoms that led to treatment with a benzodiazepines or benzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of hypnotic agent. It may be accompanied by other reactions including mood changes, anxiety and restlessness.

It is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur when the medicinal product is being discontinued.

There are indications that, in the case of benzodiazepines and benzodiazepine-like agents with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.

As the risk of withdrawal symptoms/rebound phenomena are more likely to develop after abrupt discontinuation of treatment, it is recommended to decrease the dose gradually.

Duration of treatment

The duration of treatment should be as short as possible (see section 4.2), but should not exceed 4 weeks including the tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.

It may be useful to inform the patient when treatment is started that it will be of limited duration.

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 readministered during the same night.

Amnesia

Benzodiazepines or benzodiazepine-like agents may induce anterograde amnesia. The condition usually occurs several hours after ingesting the product. In order to reduce the risk, patients should ensure that they will be able to have an uninterrupted sleep of 8 hours (see section 4.8).

Psychiatric and "paradoxical" reactions

When using benzodiazepines or benzodiazepine-like agents, reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, somnambulism, 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.

Specific patient groups

Elderly or debilitated patients should receive a lower dose: see recommended dosage (section 4.2).

Due to the myorelaxant effect there is a risk of falls and consequently of hip fractures particularly for elderly patients when they get up at night.

Patients with renal insufficiency (see section 5.2)

Although dose adjustment is not necessary, caution should be exercised.

Patients with chronic respiratory insufficiency Caution should be observed when prescribing zolpidem tartrate since benzodiazepines have been shown to impair respiratory drive. It should also be taken into consideration that anxiety or agitation have been described as signs of decompensated respiratory insufficiency.

Patients with severe hepatic impairment

Benzodiazepines and benzodiazepine-like agents are not indicated for the treatment of patients with severe hepatic impairment as they may precipitate encephalopathy.

Use in patients with psychotic illness:

Benzodiazepines and benzodiazepine-like agents are not recommended for the primary treatment.

Use in depression:

Despite the fact that relevant clinical, pharmacokinetic and pharmacodynamic interactions with SSRI have not been demonstrated, zolpidem tartrate 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 medicinal product that is feasible should be supplied to these patients.

Benzodiazepines 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 patients with a history of drug or alcohol abuse:

Benzodiazepines and benzodiazepine-like agents should be used with extreme caution in patients with a history of alcohol or drug abuse. These patients should be under careful surveillance when receiving zolpidem tartrate since they are at risk of habituation and psychological dependence.

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 of 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).

The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction with other medicinal products and other forms of interaction

Concomitant intake with alcohol is not recommended. The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Caution should be exercised when Zolpidem tartrate is used in combination with other CNS depressants (see section 4.4).

Combination with CNS depressants

Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, antiepileptic drugs, anaesthetics and sedative antihistamines. Therefore, concomitant use of zolpidem with these drugs may increase drowsiness and next-day psychomotor impairment, including impaired driving ability (see section 4.4 and section 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.

Co-administration of muscle relaxants may potentiate the muscle-relaxant effect -especially in elderly patients and at higher dosage (risk of falling!).

In the case of narcotic analgesics enhancement of euphoria may also occur leading to an increase in psychological dependence.

CYP450 inhibitors and inducers

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

Zolpidem tartrate is metabolised by some enzymes of the cytocrome P450-family.

The main enzyme is CYP3A4.

Rifampicin induces the metabolism of zolpidem tartrate, 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 (e.g. carbamazepine, and phenytoin).

Compounds that inhibit hepatic enzymes particularly CYP3A4 (e.g. azole antimycotics, macrolide antibiotics, and grapefruit juice) may increase plasma concentrations and enhance the activity of zolpidem tartrate. However, when zolpidem tartrate is administrated with itraconazol (CYP3A4 inhibitor), the pharmacokinetic and pharmacodynamic effects are not significantly different. The clinical relevance of these results is unknown.

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

Other drugs

When zolpidem tartrate was administered with warfarin, digoxin, ranitidine, no significant pharmacokinetic interactions were observed.

4.6 Pregnancy and lactation

Pregnancy

There are insufficient data to permit an assessment of the safety of Zolpidem tartrate during pregnancy.

Although animal studies have shown no teratogenic or embryotoxic effects, safety in pregnancy has not been established in humans.

Caution should be exercised when prescribing to pregnant women.

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspect that she is pregnant.

If, for compelling medical reason, zolpidem tartrate 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 took benzodiazepines or benzodiazepine-like agents chronically during the latter stages of pregnancy may develop withdrawal symptoms in the postnatal period as a result of physical dependence.

Breast-feeding

Zolpidem tartrate passes into breast milk in minimal amounts. Zolpidem tartrate should therefore not be used during breast-feeding since effects on the infant have not been investigated.

Fertility:

In a rat reproduction study, there was no effect on fertility in males or females after daily oral doses of 4 to 100 mg base/kg or 5 to 130 times the recommended human dose in mg/m².

4.7 Effects on ability to drive and use machines

Zolpidem has major influence on the ability to drive and use machines.

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 Undesirable effects

The following frequency data is the basis for the evaluation of undesirable effects:

Very common (>1/10 )

Common (>1/100 to < 1/10)

Uncommon (>1/1,000 to < 1/100 )

Rare (>1/10,000 to < 1/1,000 )

Very rare (< 1/10,000)

Not known (cannot be estimated based on available data).

There is evidence of a dose-relationship for adverse effects associated with zolpidem tartrate use, particularly for certain CNS and gastrointestinal events.

These effects seem to be related with individual sensitivity and to appear more often within the hour following the medicinal product intake if the patient does not go to bed or does not sleep immediately (see section 4.2).

Immune system disorders

Not known: angioneurotic oedema

Psychiatric disorders

Common: hallucination, agitation, nightmare Uncommon: confusional state, irritability

Not known: restlessness, aggression, delusion, anger, psychosis, abnormal behaviour, sleep walking (See Section 4.4), dependence (withdrawal symptoms, or rebound effects may occur after treatment discontinuation), libido disorder

Most of these psychiatric undesirable effects are related to paradoxical reactions

Nervous system disorders:

Common: somnolence, headache, dizziness, exacerbated insomnia, anterograde amnesia: (amnestic effects may be associated with inappropriate behaviour)

Not known: depressed level of consciousness

Eye disorders Uncommon: diplopia

Gastro-intestinal Disorders Common: diarrhoea

Hepatobiliary disorders

Not known: Liver enzymes elevated

Skin and subcutaneous tissue disorders Not known: rash, pruritus, urticaria

Musculoskeletal and connective tissue disorders Not known: muscular weakness

General disorders and administration site conditions Common: fatigue

Not known: gait disturbance, drug tolerance, fall (predominantly in elderly patients and when zolpidem was not taken in accordance with prescribing recommendation)

4.9 Overdose

In reports of overdose with zolpidem tartrate alone, impairment of consciousness has ranged from somnolence to light coma. Besides visual disturbances, dystonia, ataxia and paradoxical reactions (restlessness, hallucinations) may occur.

Individuals have fully recovered from overdoses up to 400 mg of zolpidem tartrate, 40 times the recommended dose.

General symptomatic and supportive measures should be used. Immediate gastric lavage should be used where appropriate. Intravenous fluids should be administered as needed. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Monitoring of respiratory and cardiovascular functions should be considered. Sedating drugs should be withheld even if excitation occurs.

Use of flumazenil may be considered when serious symptoms are observed. In the treatment of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.

Due to the high distribution volume and protein binding of zolpidem tartrate, haemodialysis and forced diuresis are not effective measures. Hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem tartrate is not dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and Sedatives, Benzodiazepine related drugs ATC Code: N05C F02

Zolpidem tartrate, an imidazopyridine is a benzodiazepine-like hypnotic agent. In experimental studies it was shown that it has sedative effects at lower dosages than those required to exert anticonvulsant, myorelaxant or anxiolytic effects. These effects are related to a specific agonist action at central receptors belonging to the ”GABA-omega” (BZ1 & BZ2) macromolecular receptor” complex, modulating the opening of the chloride ion channel. Zolpidem tartrate acts primarily upon omega (BZ1) receptor subtypes. The clinical relevance of this is not known.

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

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

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

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

5.2 Pharmacokinetic properties

Absorption

Zolpidem has both a rapid absorption and onset of hypnotic effect. Bioavailability is 70% following oral administration. It demonstrates linear kinetics in the therapeutic dose range. The therapeutic plasma level is between 80 and 200 ng/ml. Peak plasma concentration is reached at between 0.5 and 3 hours after administration.

Distribution

The distribution volume in adults is 0.54 //kg and decreases to 0.34 //kg in the elderly.

Protein binding amounts to 92%. First pass metabolism by the liver amounts to approximately 35%. Repeated administration has been shown not to modify protein binding indicating a lack of competition between zolpidem tartrate and its metabolites for binding sites.

Elimination

The elimination half-life is short, with a mean of 2.4 hours.

All metabolites are pharmacologically inactive and are eliminated in the urine (56%) and in the faeces (37%).

Zolpidem tartrate has been shown in trials to be non-dialysable.

Special populations

In patients with renal insufficiency, a moderate reduction in clearance is observed (independent of possible dialysis). The other pharmacokinetic parameters remain unaffected.

In elderly patients a reduced clearance has been observed. In a group of patients aged 81-95 years, the maximal plasma concentrations increased by around 80 % without a significant change in the elimination half-life.

In patients with liver cirrhosis a 5-fold increase in AUC and a 3-fold increase in halflife was observed.

5.3 Preclinical safety data

Based on conventional studies of safety pharmacology, acute and chronic toxicity, toxicity to reproduction, genotoxicity and cancerogenic potential, preclinical data do not reveal any specific risk for humans.

Foetal developmental retardations and foetotoxic effects in rats and rabbits were observed only at doses well above the maximum human dosage. There was no evidence of a teratogenic potential.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate Cellulose, microcrystalline Sodium starch glycolate (Type A) Magnesium stearate Film-Coating:

Hypromellose Macrogol 400 Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVDC-Aluminium blister Pack sizes: 4, 5, 7, 8, 10, 14, 15, 20, 25, 28, 30, 40, 50, 56, 60, 70, 80, 84, 90, 98, 100, 105, 112, 150, 250 and 500 film-coated tablets.

HDPE bottle with white opaque polypropylene stock ribbed closure. Pack sizes of 30, 50, 100, 250 and 500.

The HDPE container contains Rayon coil as an absorbent to fill the void in it. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Amneal Pharma Europe Limited 70 Sir John Rogerson’s Quay,

Dublin 2,

Ireland.

8    MARKETING AUTHORISATION NUMBER(S)

PL 42357/0137

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 11/02/2011

DATE OF REVISION OF THE TEXT

04/09/2013

DATE OF REVISION OF THE TEXT

29/08/2014