Tuesday, March 19, 2013

Clonidine HCl

Clonidine HCl
75mcg Tablet
150mcg Tablet
150mcg Ampule

Drug Category: Anti-hypertensive Drug

Brand Name: Catapres®

Clonidine HCl is indicated in the treatment of hypertension.
Clonidine HCl may be employed alone or concomitantly with other anti-hypertensive agents.
For treatment of hypertensive crisis, slow parenteral administration is especially suitable due to rapid onset of action.

Dosage and administration:
Treatment of hypertension requires regular medical supervision.
The dose of Clonidine HCl must be adjusted according to the patient's individual blood pressure response.

As an initial daily dose in mild to moderate forms of hypertension, 75mcg (or 100mcg) to 150mcg (or 200mcg) twice daily are sufficient in most cases.

After a period of 2 – 4 weeks the dose may be increased if necessary until the desired response is achieved.

Usually doses above 600mcg per day do not result in a further marked drop in blood pressure.

In severe hypertension it might be necessary to increase the single dose further to 300mcg; this could be repeated up to three times daily (900mcg).

Subcutaneous or I.M. Injection of an ampule containing 150mcg Clonidine HCl should only be carried out in patients in a lying position.

A dosage of 0.2mcg/kg/minute is recommended for IV infusion. The rate of infusion should not exceed 0.5mcg/kg/minute to avoid transient blood pressure increase. No more than 150mcg should be used per infusion. If necessary, ampules can be administered parenterally up to four times daily.

This medicinal products contains less than 1mmol sodium (23mg) per ampule, i.e. essentially 'sodium-free'.

Renal Insufficiency
Dosage must be adjusted
  • According to the individual anti-hypertensive response which can show high variability in patients with renal insufficiency.
  • According to the degree of renal impairment
Careful monitoring is required. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis..

Clonidine HCl should not be used in patients with known hypersensitivity to the active ingredient or other components of the product, and in patients with severe bradyarrhythmia resulting from either sic sinus syndrome or AV block of 2nd and 3rd degree.

In case of rare hereditary conditions that may be incompatible with an excipients of the product (please refer to “special warnings and precautions”) the use of the product is contraindicated.

Special warnings and precautions:
Clonidine HCl should be used with caution in patients with mild to moderate bradyarrhythmia such as low sinus rhythm, with disorders of cerebral or peripheral perfusion, depression, polyneuropathy and constipation. In hypertension caused by phaeochromocytoma no therapeutic effect of Clonidine HCl can be expected. Clonidine and its metabolites are extensively excreted with the urine. Renal insufficiency requires particularly careful adjustment of dosage (see Dosage and Administration). As with other anti-hypertensive drugs, treatment with Clonidine HCl should be monitored particularly carefully in patients with heart failure or severe coronary heart disease.

Patients should be instructed no to discontinue therapy without consulting their physician. Following sudden discontinuation of Clonidine HCl after prolonged treatment with high doses, restlessness, palpitations, rapid rise in blood pressure, nervousness, tremor, headache or nausea have been reported.

When discontinuing therapy with Clonidine HCl, the physician should reduce the dose gradually over 2 – 4 days.
An excessive rise in blood pressure following discontinuation of Clonidine HCl therapy can be reversed by intravenous phentolamine or tolazoline (see section Interactions).
If long-term treatment with a beta-receptor blocker has to be interrupted, then the beta-receptor blocker should first be phased out gradually and then clonidine.
Patients who wear contact lenses should be warned that treatment with Clonidine HCl may cause decreased lacrimation.
The use and safety of clonidine in children and adolescents has little supporting evidence in randomized controlled trials and therefore can not be recommended for use in this population/
In particular, when clonidine is used off-label concomitantly with methylphenidate in children with ADHS, serious adverse reactions, including death, have been observed. Therefore, clonidine in this combination is not recommended.

Tablets 75mcg or 150mcg
This product contains 205.5mg of Lactose per maximum recommended daily dose. Patients with the rare hereditary conditions of galatose intolerance e.g. galactosemia should not take this medicine.

The reduction in blood pressure induced by clonidine can be further potentiated by concurrent administration of other hypotensive agents. This can be of therapeutic use in the case of other anti-hypertensive agents such as diuretics, vasodilators, beta-receptor blockers, calcium antagonist and ACE-inhibitors, but not alpha1-blocking agents.

Substances which raise blood pressure or induce a Na+ and water retaining effect such as non-steroidal anti-inflammatory agents can reduce the therapeutic effect of clonidine.

Substances with alpha2-receptor blocking properties such as phentolamine or tolazoline may abolish the alpha2-receptor blockers mediated effects of clonidine in a dose-dependent manner.

Concomitant administration of substances with a negative chronotropic or dromotropic effect such as beta-receptor blockers or digitalis glycosides can cause or potentiate bradycardic rhythm disturbances.

It cannot be ruled out that concomitant administration of a beta-receptor blocker will cause or potentiate peripheral vascular disorders.

The anti-hypertensive effect of clonidine may be reduced or abolished and orthostatic regulation disturbances may be provoked or aggravated by concomitant administration of tricyclic antidepressants or neuroleptics with alpha-receptor blocking properties.

Based on observations in patients in a state of alcoholic delirium it has been suggested that high intravenous doses of clonidine may increase that arrhythmogenic potential (QT-prolongation, ventricular fibrillation) of high intravenous doses of haloperidol.

Causal relationship and relevance for anti-hypertensive treatment have not been established.
The effects of centrally depressant substances or alcohol can be potentiated by clonidine.

Fertility, pregnancy and lactation
There are limited amount of data from the use of clonidine in pregnant women.
During pregnancy Clonidine HCl, as any drug, should be administered if clearly needed. Careful monitoring of mother and child is recommended.
Clonidine passes the placental barrier and may lover the heart rate of the fetus.
There is no adequate experience regarding the long-term effect of prenatal exposure.
During pregnancy the oral forms of clonidine should be preferred.
Intravenous injection of clonidine should be avoided.
Non-clinical studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section Toxicology).
Post partum a transient rise in blood in the newborn cannot be excluded.

Clonidine is excreted in human milk. However, there is insufficient information on the effects on newborns. The use of Clonidine HCl is therefore not recommended during breast feeding.

No clinical studies on the effect on human fertility have been conducted with clonidine. Non-clinical studies with clonidine indicate no direct or indirect harmful effects with respect to the fertility index (see section Toxicology)

Effects on ability to drive and use machines:
No studies on the effects on the ability to drive and use machines have been performed.
However, patients should be advised that they may experience undesirable effects such as dizziness, sedation and accommodation disorder during treatment with Clonidine HCl. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

Side Effects:
Most adverse effects are mild and tend to diminish with continued therapy.

Endocrine disorders
Psychiatric disorders
confusional state, delusional perception, depression, hallucination, libido decreased, nightmare, sleep disorder
Nervous system disorders
dizziness, headache, paresthesia, sedation
Eye disorders
accommodation disorder, lacrimation decreased
Cardiac disorders
atrioventricular block, bradyarrhythmai, sinus bradycardia
Vascular disorders
orthostatic hypotension, Raynaud's phenomenon
Respiratory, thoracic and mediastinal disorders
nasal dryness
Gastrointestinal disorders
colonic pseudo-obstruction, constipation, dry mouth, nausea, salivary gland pain, vomiting
Skin and subcutaneous tissue disorders
alopecia, pruritus, rash, uricaria
Reproductive system and breast disorders
erectile dysfunctional
General disorders and administration site conditions
fatigue, malaise
blood glucose increase

Clonidine has a wide therapeutic range. Manifestations of intoxication are due to generalized sympathetic depression and include pupillary constriction, lethargy, bradycardia, hypotension, hypothermia, somnolence including coma, respiratory depression including apnea. Paradoxic hypertension cause by stimulation of peripheral alpha1-receptor may occur.

Careful monitoring and symptomatic measures.

Pharmacological Properties:
Clonidine acts primarily on the central nervous system, resulting in reduced sympathetic outflow and a decrease in peripheral resistance, renal vascular resistance, heart rate and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact and therefore orthostatic symptoms are mild and infrequent. During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise.

Absorption and distribution
The pharmacokinetics of clonidine is dose-proportional in the rage or 75 – 300mcg. Clonidine is well absorbed and undergoes a minor first pass effect.

Peak plasma concentration are reached within 1 – 3 after oral administration. The plasma protein binding is 30 – 40%.

Clonidine is rapidly and extensively distributed into tissues, and crosses the blood-brain-barrier as weel as the placental barrier. Clonidine is excreted in human milk. However, there is insufficient information on the effect on newborns.

The terminal elimination half-life of clonidine has been found to range from 5 – 25.5 hours. It can be prolonged in patients with severely impaired renal function up to 41 hours.

About 70% of the dose administered is excreted with the urine mainly in form of the unchanged parent drug (40 – 60% of dose). The main metabolite p-hydroxy-clonidine is pharmacologically inactive. Approximately 20% of the total amounts is excreted with the feces. The pharmacokinetics of clonidine is not influenced by food nor by the race of the patient.

The anti-hypertensive effect is reached at plasma concentration between about 0.2 and 2.0ng/ml in patients with normal renal function. The hypotension effect is attentuated or decreased with plasma concentration above 2.0ng/ml.

Single dose toxicity studies were performed with clonidine in different animal species by oral and parenteral routes of administration. The approximative oral LD50 values were 70mg/kg (mouse), 190mg/kg (rat), >15mg/kg (dog) and 150mg/kg in monkeys. Following subcutaneous injection, the LD50 values were >3mg/kg in dogs, 153mg/kg in rats. After intravenous administration the lethal dose ranges were between 6mg/kg (dog) and <21mg/kg (rat).

Toxic trans-species signs of toxicity following exposure to clonidine were exophthalmus, ataxia and tremor, independently from the route of administration. At lethal doses, tonic-clonic convulsions occurred. In addition, excitement and aggressiveness alternating with sedation (mouse, rat, dog), salivation and tachypnea (dog) as well as hypthermia and apathy (monkey) were observed.

In repeated oral dose toxicity studies up to 18 months clonidine was well tolerated at -0.1mg/kg (rat), 0.03mg/kg (dog) and 1.5mg/kg (monkey). In a 13 week study in rats, the no adverse effect level (NOAEL) was 0.05mg/kg rabbits and dogs tolerated 0.01mg/kg/day for 5 and 4 weeks, respectively. Higher dosages caused hyperactivity, aggression, reduced food consumption and body weight gain (rat), sedation (rabbit) or an increase in heart and liver weight accompanied by elevated serum GPT, alkaline phosphatase and alpha-globulin levels and focal liver necroses (dog).

There were no signs of any teratogenic potential after oral administration in mouse and rat at 2.0mg/kg and rabbit at 0.09 mg?kg or after SC (0.015mg/kg, rat) and IV treatment (0.15mg/kg, rabbit). In rats, increases in resorption rate were observed at oral dosage of >0.015mg/kg/day; however dependent on duration of dosing.
Fertility in rats was not impaired up to 0.15mg/kg. Doses up to 0.075mg/kg did not affect the peri- and postnatal development of the progeny.

There was no mutagenic potential in Ames and micronucleus assay in mice. Clonidine was not tumorgenic in a carcinogenecity in rats. No local irritating or sensitizing potential was found in guinea pigs and rabbits following IV and IA administrations.

Storage Conditions:
Store at temperature not exceeding 30oC.

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