Zolpirest M

Uses

Melatonin is used for numerous conditions but is showing the most promise in short-term regulation of sleep patterns, including jet lag.

Insomnia: Melatonin helps to induce sleep in people with-

• Disrupted circadian rhythms (such as those suffering from jet lag or poor vision or those who work the night shift)
• Low melatonin levels (such as some elderly and individuals with schizophrenia)
• Children with learning disabilities who suffer from insomnia.

Osteoporosis: Melatonin stimulates cells called osteoblasts that promote bone growth.

In Menopause:

Melatonin helps peri- or postmenopausal women to regulate sleep patterns.

Eating disorders: Melatonin levels may play a role in the symptoms of anorexia.

Sarcoidosis:

Sarcoidosis is an inflammatory disease that affects multiple organs in the body, but mostly the lungs and lymph glands.

Attention Deficit Hyperactivity Disorder (ADHD): It may be effective in managing sleep disturbances in children with this condition

Zolpidem is used for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem has been shown to decrease sleep latency for up to 35 days in controlled clinical studies The clinical trials performed in support of efficacy were 4-5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

Zolpirest M is also used to associated treatment for these conditions: InsomniaInsomnia

How Zolpirest M works

Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cylcase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but it also activates phosphilpase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signallling cascades have various effects in the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types.The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic substance with a chemical structure that is not related to the structure benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs exerting hypnotic effects. It interacts with a GABA-BZ receptor complex and shares various pharmacological properties with the benzodiazepine class of drugs .

Subunit binding of the GABAA receptor chloride channel macromolecular complex is thought to lead to the sedative, anticonvulsant, anxiolytic, and myorelaxant drug effects of zolpidem. The main regulatory site of the GABAA receptor complex can be found on its alpha (α) subunit and is called the benzodiazepine (BZ) or omega (ω) receptor. At least three different subtypes of the (ω) receptor have been identified to this date .

In contrast to benzodiazepine drugs, which are found to modulate all benzodiazepine receptor subtypes in a non-selective fashion, zolpidem binds the (BZ1) receptor specifically with a potent affinity for the alpha 1/alpha 5 subunits (in vitro) . More recent studies suggest that zolpidem binds primarily to the alpha 1, 2, and 3 subunits of the GABA receptor , , , and not the alpha 5 subunit.

The (BZ1) receptor is found primarily on the Lamina IV of the brain sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. Specific and selective binding of zolpidem on the (BZ1) receptor is not considered absolute, however, this binding could potentially explain the relative lack of myorelaxant and anticonvulsant activity in animal studies in addition to the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses .

Dosage

Zolpirest M dosage

Adult-

Insomnia: 3-6 mg one hour before bedtime

Jet lag: 0.50 to 5 mg one hour prior to bedtime at final destination or, 1 to 5 mg 1 hour before bedtime for 2 days prior to departure and for 2 to 3 days upon arrival at final destination.

• Eastbound travel: Take a preflight early evening treatment followed by treatment at bedtime for 4 days after arrival.
• Westbound travel: Take for 4 days at bedtime when in the new time zone.

Sarcoidosis:

20 mg per day for 4 to 12 months.

Depression: 0.125 mg twice in the late afternoon, each dose 4 hours apart.

Difficulty falling asleep: 5 mg 3 to 4 hours before an imposed sleep period over a 4-weeks period.

Children-

6 months to 14 years of age with sleep disorders: 0.30 mg/day

Dosage In Adults: Use the lowesteffective dosefor the patient. The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7–8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next day impairment of driving and other activities that require full alertness. The total dose of Zolpidem should not exceed 10 mg once daily immediately before bedtime. Zolpidem should be taken as a single dose and should not be readministered during the same night.The recommended initial doses for women and men are different because zolpidem clearance is lower in women.Special Populations: Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The recommended dose of Zolpidem in these patients is 5 mg once daily immediately before bedtimePatients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal subjects. The recommended dose of Zolpidem in these patients is 5 mg once daily immediately before bedtime. Avoid Zolpidem use in patients with severe hepatic impairment as it may contribute toencephalopathyUse With CNS Depressants: Dosage adjustment may be necessary when Zolpidem is combined with other CNS depressant drugs because of the potentially additive effects

The effect of Zolpidem may be slowed by ingestion with or immediately after a meal.

Side Effects

Increased seizure activity; drowsiness, headache. Disruption of normal circadian rhythm. May worsen symptoms for individuals with depression.

Atypical thinking and behaviour, hallucination, nightmare, somnolence, somnambulism, headache, nausea, vomiting, dizziness, vertigo, drowsiness, asthenia, ataxia, rebound insomnia, amnesia, GI disturbances, upper and lower respiratory tract infection, fatigue, visual disturbances, increased ALT serum concentrations, abnormal LFT.

Toxicity

Generally well-tolerated when taken orally. The most common side effects, day-time drowsiness, headache and dizziness, appear to occur at the same frequency as with placebo. Other reported side effects include transient depressive symptoms, mild tremor, mild anxiety, abdominal cramps, irritability, reduced alertness, confusion, nausea, vomiting, and hypotension. Safety in Adults: Evidence indicates that it is likely safe to use in oral and parenteral forms for up to two months when used appropriately. Some evidence indicates that it can be safely used orally for up to 9 months in some patients. It is also likely safe to use topically when used appropriately. Safety in Children: Melatonin appeared to be used safely in small numbers of children enrolled in short-term clinical trials. However, concerns regarding safety in children have arisen based on their developmental state. Compared to adults over 20 years of age, people under 20 produce high levels of melatonin. Melatonin levels are inversely related to gonadal development and it is thought that exogenous administration of melatonin may adversely affect gonadal development. Safety during Pregnancy: High doses of melatonin administered orally or parenterally may inhibit ovulation. Not advised for use in individuals who are pregnant or trying to become pregnant. Safety during Lactation: Not recommended as safety has not be established.

Oral, rat: LD₅₀ ≥3200 mg/kg

Oral (male rat) LD₅₀ = 695 mg/kg .

Overdose

Symptoms of overdose include impairment of consciousness ranging from somnolence to light coma, in addition to cardiorespiratory collapse resulting in fatal outcomes have been reported .

Withdrawal effects

Following rapid decreases in dose or abrupt discontinuation of zolpidem and other sedative/hypnotics, reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs have been made .

Carcinogenesis

Zolpidem was administered to rats and mice over a span of 2 years at dietary dosages of 4, 18, and 80 mg/kg/day. In mice, these doses are considered 26 to 520 times or 2 to 35 times the maximum 10 mg human dose, respectively. In rats, these doses are 43 to 876 times or 6 to 115 times the maximum 10 mg human dose. No evidence of carcinogenicity was seen in mice. Renal liposarcomas were observed in 4/100 rats (3 males, 1 female) receiving 80 mg/kg/day, and a renal lipoma was observed in one male rat at the 18 mg/kg/day dose. Incidence rates of lipoma and liposarcoma for zolpidem were similar to those seen in historical control cases, and the tumor findings are presumed to be a spontaneous occurrence, not causally related to zolpidem .

Mutagenesis

Zolpidem did not show mutagenic activity in several tests including the Ames test, genotoxicity in mouse lymphoma cells in vitro, chromosomal aberrations in cultured human lymphocytes, abnormal DNA synthesis in rat hepatocytes in vitro, and the micronucleus test performed in mice .

Impairment of fertility

In a rat reproduction study, the high dose (100 mg base/kg) of zolpidem lead to irregular estrus cycles and prolonged precoital intervals, however, there was no effect on male or female fertility after daily oral doses comparable to 5 to 130 times the recommended human dose. No effects on any other fertility parameters were observed .

Use in pregnancy

This drug is considered a pregnancy category C drug. There are currently no sufficient conclusive studies completed in pregnant women to determine the safety of zolpidem use during pregnancy. Zolpidem should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Use in nursing

From 0.004% to 0.019% of the total administered zolpidem dose is excreted into milk. The effect of zolpidem on the nursing infant is unknown at this time. Caution should be observed when zolpidem is administered to a nursing mother .

Precaution

Caffeine and fluvoxamine may increase the effects of melatonin, while melatonin may decrease the antihypertensive effect of nifedipine.

Obstructive sleep apnoea, myasthenia gravis, compromised respiratory function. Patients exhibiting symptoms of depression. History of drug or alcohol abuse. Avoid abrupt withdrawal and rapid dose reduction after prolonged therapy. Re-evaluate if insomnia fail to remit after 7-10 days as this may indicate the presence of underlying psychiatric and/or medical condition. Pregnancy, lactation, childn <18 yr.

Interaction

Antidepressant Medications: Melatonin reduces the antidepressant effects of desipramine and fluoxetine. In addition, fluoxetine leads to measurable depletion of melatonin in people.

Antipsychotic Medications: People with schizophrenia and tardive dyskinesia taking antipsychotic medications with melatonin has significantly reduced mouth movements compared to those who did not take the supplements.

Benzodiazepines: The combination of melatonin and triazolam improves sleep quality. In addition, there have been a few reports suggesting that melatonin supplements may help individuals stop using long-term benzodiazepine therapy.

Blood Pressure Medications: Melatonin may reduce the effectiveness of blood pressure medications like methoxamine and clonidine. In addition, calcium channel blockers (such as nifedipine, verapamil, diltiazem, amlodipine, nimodipine, felodipine, nisoldipine, and bepridil) may decrease melatonin levels. Use of beta-blockers (propranolol, acebutolol, atenolol, labetolol, metoprolol, pindolol, nadolol, sotalol, and timolol) may reduce melatonin production in the body.

Blood-Thinning Medications, Anticoagulants: Melatonin may increase the risk of bleeding from anticoagulant medications such as warfarin.

Interleukin 2: In one study of 80 cancer patients, use of melatonin in conjunction with interleukin-2 led to more tumor regression and better survival rates than treatment with interleukin-2 alone.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs): NSAIDs such as ibuprofen may reduce the levels of melatonin in the blood.

Steroids and Immunosuppressant Medications: People should not take melatonin with corticosteroids or other medications used to suppress the immune system because the supplement may cause them to be ineffective.

Tamoxifen: Preliminary research suggests that the combination of tamoxifen (a chemotherapy drug) and melatonin may benefit certain patients with breast and other cancers.

Other Substances: Caffeine, tobacco, and alcohol can all diminish levels of melatonin in the body while cocaine and amphetamines may increase melatonin production.

Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression. Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor impairment, including impaired driving ability. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs.Imipramine, Chlorpromazine: Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance Haloperidol: A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict the absence of an effect following chronic administration Alcohol: An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated Sertraline: Concomitant administration of zolpidem and sertraline increases exposure to zolpidemFluoxetine: After multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance

Volume of Distribution

0.54 to 0.68 L/kg (in humans) . In patients with long term renal insufficiency who were not yet on hemodialysis, the volume of distribution was found to increase significantly, AUC increased by 60%, and half-life nearly doubled .

Elimination Route

The absorption and bioavailability of melatonin varies widely.

Zolpidem is rapidly absorbed from the gastrointestinal tract. In a single-dose crossover study in 45 healthy subjects given 5 and 10 mg zolpidem tartrate tablets, the average peak zolpidem concentrations (Cmax) were 59 and 121 ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both doses .

Half Life

35 to 50 minutes

The average zolpidem elimination half-life was 2.6 and 2.5 hours, for the 5 and 10 mg tablets, respectively .

Clearance

In a clinical trial, after a 20mg dose, total clearance of zolpidem 0.24 to 0.27 ml/min/kg .

Elimination Route

Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated mainly by renal excretion .

Pregnancy & Breastfeeding use

Information regarding safety and efficacy in pregnancy and lactation is not available.

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Melatonin should not be used by patients who have autoimmune diseases.

Severe hepatic impairment.

Special Warning

Pediatric Use: Zolpidem is not recommended for use in children. Safety and effectiveness of zolpidem in pediatric patients below the age of 18 years have not been established.

Acute Overdose

There is little or no evidence of any major toxicities with melatonin, even at high doses.

Symptoms: Drowsiness, impairment of consciousness from somnolence to coma, compromised CV and respiratory function. Management: Treatment is largely symptomatic and supportive. IV fluids should be administered as needed. Activated charcoal may be given if presented w/in 1 hr of ingestion of >1 mg/kg zolpidem in adults or childn. Gastric lavage may be considered if presented w/in 1 hr of ingestion of >100 mg zolpidem and monitor for at least 12 hr. Flumazenil may be used if there is severe CNS depression, but generally not needed. Haemodialysis is unlikely to be useful.

Storage Condition

Store in a cool & dry place, protected from light & moisture.

Store between 20-25° C.

Innovators Monograph

You find simplified version here Zolpirest M