Helinase

Uses

Adults:

• Schizophrenia: treatment of symptoms and prevention of relapse (oral and IM)
• Other psychoses, especially paranoid (oral and IM)
• Mania and hypomania(oral and IM)
• Mental or behavioural problems such as aggression, hyperactivity and self- mutilations in the mentally retarded and in patients with organic brain damage
• As an adjunct to short-term management of moderate to severe psychomotor agitation, excitement, violent or dangerously impulsive behavior (oral and IM)
• Intractable hiccup (oral)
• Restlessness and agitation in the elderly (oral)
• Gilles de la Tourette syndrome and severe tics (oral)
• Nausea and vomiting (IM)

Children (Oral administration only):

• Childhood behavioral disorders especially when associated with hyperactivity and aggression
• Gilles de la Tourette syndrome
• Childhood schizophrenia

Helinase is also used to associated treatment for these conditions: Chemotherapy-Induced Nausea and Vomiting (CINV), Delirium, Gilles de la Tourette's Syndrome, Huntington's Disease (HD), Obsessive Compulsive Disorder (OCD), Psychosis, Schizophrenia, Aggressive reaction, Severe Hyperactivity, Severe disruptive behaviour disorder

How Helinase works

While haloperidol has demonstrated pharmacologic activity at a number of receptors in the brain, it exerts its antipsychotic effect through its strong antagonism of the dopamine receptor (mainly D2), particularly within the mesolimbic and mesocortical systems of the brain. Schizophrenia is theorized to be caused by a hyperdopaminergic state within the limbic system of the brain. Dopamine-antagonizing medications such as haloperidol, therefore, are thought to improve psychotic symptoms by halting this over-production of dopamine. The optimal clinical efficacy of antipsychotics is associated with the blockade of approximately 60 % - 80 % of D2 receptors in the brain.

While the exact mechanism is not entirely understood, haloperidol is known to inhibit the effects of dopamine and increase its turnover. Traditional antipsychotics, such as haloperidol, bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. It is believed that haloperidol competitively blocks post-synaptic dopamine (D2) receptors in the brain, eliminating dopamine neurotransmission and leading to the relief of delusions and hallucinations that are commonly associated with psychosis. It acts primarily on the D2-receptors and has some effect on 5-HT2 and α1-receptors, with negligible effects on dopamine D1-receptors. The drug also exerts some blockade of α-adrenergic receptors of the autonomic system.

Antagonistic activity regulated through dopamine D2 receptors in the chemoreceptive trigger zone (CTZ) of the brain renders its antiemetic activity. Of the three D2-like receptors, only the D2 receptor is blocked by antipsychotic drugs in direct relation to their clinical antipsychotic abilities.

Clinical brain-imaging findings show that haloperidol remains tightly bound to D2 dopamine receptors in humans undergoing 2 positron emission tomography (PET) scans with a 24h pause in between scans. A common adverse effect of this drug is the development of extrapyramidal symptoms (EPS), due to this tight binding of haloperidol to the dopamine D2 receptor.

Due to the risk of unpleasant and sometimes lifelong extrapyramidal symptoms, newer antipsychotic medications than haloperidol have been discovered and formulated. Rapid dissociation of drugs from dopamine D2 receptors is a plausible explanation for the improved EPS profile of atypical antipsychotics such as Risperidone. This is also consistent with the theory of a lower affinity for D2 receptors for these drugs. As mentioned above, haloperidol binds tightly to the dopamine receptor, potentiating the risk of extrapyramidal symptoms, and therefore should only been used when necessary.

Dosage

Helinase dosage

Oral Administration-

Adults: Schizophrenia, Psychoses, Mania and Hypomania, Mental or behavioral problems, Psychomotor agitation, Excitement, Violent or dangerously impulsive behavior, Organic brain damage.Initial dosage:

• Moderate symptomatology 1.5-3.0 mg bd or tds.
• Severe symptomatology/resistant patients 3.0-5.0 mg bd or tds. The same starting doses may be employed in adolescents, who in certain cases, may require up to 30 mg or exceptionally up to 60 mg/day
• In resistant schizophrenics daily dosages up to 100 mg (or rarely up to 120 mg) may be necessary to achieve an optimal response.

Maintenance dosage:

• Once satisfactory control of symptoms has been achieved dosage, dosage should be gradually reduced to the lowest maintenance dose, often as low as 5 mg/day. Too rapid a dosage reduction should be avoided.
• Restlessness or agitation in elderly: Initial dose 1.5- 3.0 mg bd or tds titrated to attain an effective maintenance dose (1.5-5.0 mg daily)
• Gilles de la tourette syndrome/Severe tics/Intractable hiccup: Starting dose1.5 mg tds adjusted according to response. A daily maintenance dose of 10 mg may be required in Gilles de la tourette syndrome.

Children:

• Childhood behavioural disorder/schizophrenia: Total daily maintenance dose of 0.025-0.05 mg/kg/day. Half the total dose should be given in the morning and the other half in the evening, up to a maximum of 10 mg daily. Not recommended for parenteral use in children.

Parenteral Administration-

Administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. The maximum dose is 20 mg/day.

Dosage for all indications should be individually determined and is best initiated and titrated under close clinical supervision. To determine the initial dose consideration should be given to the patients age, severity of symptoms and previous response to other neuroleptics. The normal starting dose should be halved, followed by a gradual titration to achieve an optimal response.

Side Effects

Extrapyramidal symptoms, acute dystonia, parkinsonian rigidity, tremor, oculogyric crises and laryngeal dystonia, confusional states or epileptic fits, depression, sedation, agitation, drowsiness, insomnia, headache, vertigo and apparent exacerbation of psychotic symptoms, nausea, loss of appetite, constipation and dyspepsia, dry mouth as well as excessive salivation, blurred vision, urinary retention have been reported.

Toxicity

Acute oral toxicity (LD50): 71 mg/kg in rats .

Precaution

Caution is advised in patients with liver disease, renal failure, epilepsy and conditions predisposing to epilepsy (e.g. alcohol withdrawal and brain damage) or convulsions. Helinase should only be used with great caution in patients with disturbed thyroid function.

Interaction

Helinase has been reported to interfere with the anticoagulant properties of phenindione in an isolated case and the possibility should be kept in mind of a similar effect occurring when haloperidol is used with other anticoagulants. Helinase may antagonize the action of epinephrine and other sympathomimetic agents and reverse the blood pressure-lowering effects of adrenergic-blocking agents, such as guanethidine. Enhanced CNS effects may occur when haloperidol is used in combination with methyldopa. Helinase inhibits the metabolization of tricyclic antidepressants, thereby increasing plasma levels of these drugs. This may result in increased tricyclic antidepressant toxicity (anticholinergic effects, cardiovascular toxicity, lowering of seizure threshold). Helinase may impair the antiparkinson effects of levodopa. If an antiparkinson agent is used concomitantly with haloperidol, both drugs should not be discontinued simultaneously, since extrapyramidal symptoms may occur due to the slower excretion rate of haloperidol.

Food Interaction

• Avoid alcohol. Alcohol may potential hypotension and CNS adverse effects.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Helinase Drug Interaction

Major: escitalopram, escitalopram, quetiapine, quetiapine, sertraline, sertralineModerate: aripiprazole, aripiprazole, lorazepam, lorazepam, divalproex sodium, divalproex sodiumUnknown: acetaminophen, acetaminophen, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Helinase Disease Interaction

Major: dementia, hyperthyroidism, parkinsonism, CNS depression/coma, related psychosis, previous neuroleptic malignant syndrome (NMS), seizure disorders, acute alcohol intoxication, cardiovascular disease, CNS depression, NMS, tardive dyskinesiaModerate: seizure, alcohol, cardiovascular disease, QT prolongation, renal/liver disease, hyperprolactinemia/breast cancer, neutropenia, dehydration, hyperprolactinemia

Volume of Distribution

The apparent volume of distribution was found to range from 9.5-21.7 L/kg. This high volume of distribution is in accordance with its lipophilicity, which also suggests free movement through various tissues including the blood-brain barrier.

Elimination Route

Helinase is a highly lipophilic compound and is extensively metabolized in humans, which may cause a large interindividual variability in its pharmacokinetics.

Studies have found a wide variance in pharmacokinetic values for orally administered haloperidol with 1.7-6.1 hours reported for time to peak plasma concentration (tmax), 14.5-36.7 hours reported for half-life (t1⁄2), and 43.73 μg/L•h [range 14.89-120.96 μg/L•h] reported for AUC. Helinase is well-absorbed from the gastrointestinal tract when ingested orally, however, the first-pass hepatic metabolism decreases its oral bioavailability to 40 - 75%.

After intramuscular administration, the time to peak plasma concentration (tmax) is 20 minutes in healthy individuals or 33.8 minutes in patients with schizophrenia, with a mean half-life of 20.7 hours. Bioavailability following intramuscular administration is higher than that for oral administration.

Administration of haloperidol decanoate (the depot form of haloperidol for long-term treatment) in sesame oil results in slow release of the drug for long-term effects. The plasma concentrations of haloperidol gradually rise, reaching its peak concentration at about 6 days after the injection, with an apparent half-life of about 21 days. Steady-state plasma concentrations are achieved after the third or fourth dose.

Half Life

Following oral administration, the half-life was found to be 14.5-36.7 hours. Following intramuscular injection, mean half-life was found to be 20.7 hours.

Clearance

Following intravenous administration, the plasma or serum clearance (CL) was found to be 0.39-0.708 L/h/kg (6.5 to 11.8 ml/min/kg). Following oral administration, clearance was found to be 141.65 L/h (range 41.34 to 335.80 L/h).

Helinase clearance after extravascular administration ranges from 0.9-1.5 l/h/kg, however this rate is reduced in poor metabolizers of CYP2D6 enzyme. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia .

Genetic polymorphism of CYP2D6 has been demonstrated to be an important source of inter-patient variability in the pharmacokinetics of haloperidol and may affect therapeutic response and incidence of adverse effects.

Elimination Route

In radiolabeling studies, approximately 30% of the radioactivity is excreted in the urine following a single oral administration of 14C-labelled haloperidol, while 18% is excreted in the urine as haloperidol glucuronide, demonstrating that haloperidol glucuronide is a major metabolite in the urine as well as in plasma in humans.

Pregnancy & Breastfeeding use

There is no proven harmful effect in the first trimester, however there have been some reports of limb malfonnations, so the drug is best avoided if possible. The principal hazard in late pregnancy is extrapyramidal adverse effects in the neonate. The drug is excreted only in trace amounts and sedation or extrapyramidal rigidity in the neonate can occur but is rarely a problem.

Contraindication

Comatose states; CNS depression; Parkinson's disease; known hypersensitivity to haloperidol; lesions of the basal ganglia.

Acute Overdose

In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: severe extrapyramidal reactions, hypotension or sedation.The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state.

Storage Condition

Store at 15-30° C.

Innovators Monograph

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