Clonidine

Clonidine is an antihypertensive and antipsychotic agent belonging to the Alpha-2-Adrenergic agonist class.

Clonidine is approved for the treatment of Hypertension, Attention deficit hyperactivity disorder (ADHD), Tourette syndrome, adjunct therapy for severe cancer-related pain, and as an adjunct in a neonatal opioid withdrawal syndrome. It is also used for management of withdrawal symptoms from opioids, benzodiazepines, and alcohol and treating anxiety, insomnia, and post-traumatic stress disorder.

Clonidine appeared to be well-absorbed from the gastrointestinal tract with bioavailability of 70-80% for immediate-release and approx 89% for extended release, and approx 60% for transdermal. It crosses the placenta and enters the breast milk where it distributes readily into extravascular sites with volume of distribution of Approx 2.9 L/kg. The plasma protein binding of clonidine is 20-40%. It gets metabolized in the liver to inactive metabolites; undergoes enterohepatic recirculation. It gets excreted via urine (40-60% as unchanged drug); feces (approx 20%) with elimination half-life of 12-16 hours; 22 ± 15 hours (epidural), and approx. 20 hours (transdermal).

The common side effects associated with Clonidine include Abdominal pain, vomiting, diarrhea, Xerostomia ; headache, dizziness, drowsiness;sexual dysfunction; itching or rash; stuffy nose, nosebleeds, etc.

Clonidine is available in the form of dosage forms such as tablets, injection, and patches.

Clonidine is available in India, USA, UK, Germany, Australia.

Clonidine belonging to the Alpha-2-Adrenergic agonist which acts as an Antihypertensive and Antipsychotic agent. Clonidine works by blocking chemicals in brain that trigger sympathetic nervous system activity, reducing the length of the detox process.

Clonidine functions through agonism of alpha-2 adrenoceptors which have effects such as lowering blood pressure, sedation, and hyperpolarization of nerves. It has a long duration of action as it is given twice daily and the therapeutic window is between 0.1mg and 2.4mg daily.

The onset of action of Clonidine occurs with Immediate-release of 0.5-1 hour; 2-4 hours for maximum reduction in blood pressure. For Transdermal: 2-3 days (initial); approx 3 days (steady state).

The Duration of Action for Clonidine in the body is 3-5 hours.

The Tmax was found within 1-3 hours for immediate-release; 7-8 hours for extended-release following the administration of Clonidine and the Cmax was 400.72pg/mL.

Clonidine is available in the dosage forms such as tablets, injection and patch.

• Tablets:

Clonidine tablets are to be swallowed whole with water.Clonidine comes as a tablet to be taken by mouth. It is usually taken 2 times a day.

• Injection:

Clonidine injection is given around the clock (continuous) using an infusion pump attached to a catheter placed into space around the spinal cord.

• Skin Patch

Wash the hands with soap and water before and after applying a patch. Do not touch the eyes and use cleaned wash hands. Do not try to trim or cut adhesive patch to adjust the dosage.

Gently wash the area of skin where the patch will applied with soap and water. Rinse the skin completely and dry with a clean, dry tissue. Apply the patch right away after removing it from the pouch.

Do not cut it into smaller pieces and do not touch the sticky surface of the patch. Apply the patch to a clean, dry, and intact skin area on the upper, outer arm or upper chest.

Choose an area with little or no hair that is free of scars, cuts, or irritation. Avoid putting the patch on skin areas where it could be rubbed off by tight clothing. Press the patch firmly in place with the fingertips to make sure that the edges stick well.

The patch should stay in place during showering, bathing, or swimming for a full 7 days.

If the patch becomes loose, press the edges against the skin and cover the patch with one of the white adhesive covers that are included in the package.

Apply a new patch if the first one becomes too loose or falls off. It is best to apply each patch to a different area of the skin to prevent skin irritation.

Clonidine is an antihypertensive and antipsychotic agent belonging to the Alpha-2-Adrenergic agonist class.

Clonidine is approved for the treatment of Hypertension, Attention deficit hyperactivity disorder (ADHD), Tourette syndrome, adjunct therapy for severe cancer-related pain and as an adjunct in neonatal opioid withdrawal syndrome. It is also used for the treatment in managing withdrawal symptoms from opioids, benzodiazepines, and alcohol and treating anxiety, insomnia, and post-traumatic stress disorder.

Clonidine is approved for use in the following clinical indications.

• Hypertension
• Treatment of attention deficit hyperactivity disorder (ADHD) in children (FDA approval 2010 for the extended-release dose form) .
• Management of tics commonly found with Tourette syndrome.
• Adjunct therapy for severe cancer-related pain.
• As an adjunct in neonatal opioid withdrawal syndrome.

Although not approved, there have been certain off-label uses documented for Clonidine. These include:

• Managing withdrawal symptoms from opioids
• Benzodiazepines
• Alcohol
• Treating Anxiety
• Insomnia and
• Post-Traumatic Stress Disorder (PTSD).

Clonidine is available in the form of dosage forms such as tablets, injection and patch.

• Hypertension

For Oral Dosage (immediate-release-tablets)

Initially, 0.1 mg PO twice daily. Increase by 0.1 mg/day at weekly intervals until desired effect is achieved (usual range: 0.2 to 0.6 mg/day). For unequal doses, taking larger portion of the daily dose at bedtime may reduces it adverse events. Although the recommendation are a maximum dose of 2.4 mg/day, which is rarely used, further antihypertensive benefit may not be achieved at doses above 1.2 mg/day. Geriatric patients may require a lower initial dose due to increased risk of side effects.

For Transdermal dosage

Initially, apply one Patch (delivers 0.1 mg/24 hours) patch to an intact area of hairless skin on the upper arm or torso, once every 7 days. Adjust dose every 1 to 2 weeks by changing or combining dosage systems. Doses above two patches are usually not associated with increased efficacy. When applying a new patch, a different area of skin should be used. Because the effects of the transdermal system may not be evident for several days after the initial administration, it is recommended that previous antihypertensive medications be continued and gradually reduced.

• Attention-Deficit Hyperactivity Disorder (ADHD)

For Immediate release tablet

Initially, 0.1 mg taken orally at bedtime, then titrate by increments of 0.1 mg/day to 0.1 mg taken orally twice daily, then 0.1 mg taken orally 3 times per day, then 0.1 mg taken orally 4 times per day. Max: 0.4 mg/day. In a 16-week, multicenter, randomized, controlled clinical trial of patients with ADHD and a chronic tic disorder (n = 136), clonidine doses were 0.25 mg/day taken orally (alone) and 0.28 mg/day taken orally The greatest ADHD benefit and improved tic severity compared to baseline was seen with the combined treatment of clonidine plus methylphenidate. Worsening of tics occurred in 20% to 26% of each treatment group, including placebo. Sedation was common (28%) in the clonidine groups.

For Transdermal patch:

Initial dosing recommendations for pediatric patients are not available; however, it has been suggested that once patients are stabilized on an oral dose they may be converted to the transdermal patch that provides an approximately equivalent daily dose (e.g., 0.1, 0.2, or 0.3 mg/day). Patches are changed once every 7 days in adults; however, due to variable absorption in pediatric patients, patches may need to be changed earlier (i.e., every 5 days). Partial doses of patches may be administered by placing impermeable material (e.g., adhesive bandage) on the skin under the patch proportionate to the desired dose reduction.

• Management of tics commonly found with Tourette syndrome.

Initially, 0.025 to 0.05 mg/day take orally. Gradually titrate according to blood pressure and heart rate. Range: 0.025 to 0.6 mg/day taken orally. Max: 0.6 mg/day taken orally, usually given in 3 to 4 divided doses. Clonidine is recommended in evidence-based guidelines (strong recommendation, moderate-quality evidence). Consider a dose reduction in elderly patients, as they may be more sensitive to adverse effects at the usual dosages. The American Academy of Neurology practice guideline states that clonidine is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; weigh the benefits of treatment against the risks (e.g., sedation, hypotension). For those with comorbid attention-deficit hyperactivity disorder (ADHD), clonidine may provide benefits for both conditions.

• Adjunct therapy for severe cancer-related pain.

Epidural dosage

Initially, 30 mcg/hour by continuous epidural infusion in combination with opioid analgesics, is recommended. Dosage may be titrated up or down depending on pain relief and occurrence of adverse events; however, there is limited experience above the maximum rate of 40 mcg/hour. In clinical trials, bolus doses of epidural clonidine range from 100 to 900 mcg per dose. The dosage should be titrated to pain relief and incidence of side effects. Consider dosage reduction in elderly patients, as they may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

• Opioid withdrawal syndrome

For Oral Dosage

The usual initial dose for opiate agonist withdrawal is 0.1 mg to 0.2 mg PO, with titration to a maximum total dose of 1 mg/day PO, administered in two to four divided doses, according to response and tolerability (e.g., blood pressure). Maximal doses are generally administered for two to four days after cessation of the opiate during the time of maximal withdrawal. Clonidine doses are then tapered, and the drug is discontinued 7 to 10 days after cessation of the opiate. The American Psychiatric Association (APA) practice guidelines for substance abuse disorders state that an initial dose of clonidine 0.1 mg PO three times (total 0.3 mg per 24 hours) is usually sufficient to suppress signs of opiate withdrawal. Use of higher doses may be acceptable during inpatient detoxification since medical staff can monitor for hypotension and sedation. Adjust subsequent dosing until withdrawal symptoms are reduced. Hold the dose if blood pressure falls below 90/60 mmHg, and resume when BP returns to normal. The APA guidelines recommend limiting outpatient dispensing for unsupervised use to a 3-day supply of clonidine because treatment requires careful dose titration and clonidine overdoses can be life-threatening. Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage and may require lower dosages. Clonidine appears generally inferior to buprenorphine or methadone taper for opiate withdrawal treatment; however, clonidine is more effective than placebo and a useful alternative to buprenorphine for targeting noradrenergic-mediated withdrawal symptoms such as nausea, vomiting, diarrhea, cramps, and sweating.

• For treatment of Alcohol Withdrawl

For Immediate Release tablets.

Initially, 0.025 to 0.05 mg/day taken orally. Gradually titrate according to blood pressure and heart rate. Range: 0.025 to 0.6 mg/day taken orally. Max: 0.6 mg/day taken orally, usually given in 3 to 4 divided doses. Clonidine is recommended in evidence-based guidelines (strong recommendation, moderate-quality evidence). Consider a dose reduction in elderly patients, as they may be more sensitive to adverse effects at the usual dosages. The American Academy of Neurology practice guideline states that clonidine is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; weigh the benefits of treatment against the risks (e.g., sedation, hypotension). For those with comorbid attention-deficit hyperactivity disorder (ADHD), clonidine may provide benefits for both conditions.

For Oral dosage (extended-release tablets)

Initially 0.1 mg/day taken orally at bedtime. Increase the dose in 0.1 mg/day increments weekly as needed to attain the desired response (Max: 0.4 mg/day). Divide doses larger than 0.1 mg/day into 2 doses taken in the morning and at bedtime. If the morning and bedtime doses are not equal, the larger dose should be given at bedtime. The American Academy of Neurology practice guideline states that clonidine is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; weigh the benefits of treatment against the risks (e.g., sedation, hypotension). For those with comorbid attention-deficit hyperactivity disorder (ADHD), clonidine may provide benefits for both conditions.

For Transdermal dosage

Initial dosing recommendations for pediatric patients are not available; however, some patients stabilized on an oral dose may then be converted to the transdermal patch that provides an approximately equivalent daily dose (i.e., 0.1, 0.2, or 0.3 mg/day). Patches are changed once every 7 days in adults; however, due to variable absorption, patches may need to be changed earlier (i.e., every 5 days) in pediatric patients. Partial doses of patches may be administered by placing impermeable material (e.g., adhesive bandage) on the skin under the patch proportionate to the desired dose reduction. The American Academy of Neurology practice guideline states that clonidine is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; weigh the benefits of treatment against the risks (e.g., sedation, hypotension). For those with comorbid attention-deficit hyperactivity disorder (ADHD), clonidine may provide benefits for both conditions. The effect size of clonidine on tics appears larger in children with tics and ADHD compared to individuals with tics and without ADHD.

Clonidine can be administered orally before/ after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Clonidine is available in various dosage strengths as 0.1 mg; 0.2 mg; 0.3 mg; 0.1 mg/24 hr; 0.2 mg/24 hr; 0.3 mg/24 hr; 100 mcg/mL; 500 mcg/mL; 0.1 mg/12 hr; 0.17 mg/24 hr; 0.09 mg/mL; 0.2 mg/12 hr.

Clonidine is available in the form of tablets, patch and injections

Clonidine is approved for the treatment of Hypertension, Attention deficit hyperactivity disorder (ADHD), Tourette syndrome, adjunct therapy for severe cancer-related pain and as an adjunct in neonatal opioid withdrawal syndrome. It is also used for the treatment in managing withdrawal symptoms from opioids, benzodiazepines, and alcohol and treating anxiety, insomnia, and post-traumatic stress disorder.

Hypertension:

It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

Attention Deficit Hyperactivity Disorder (ADHD):

• Regularly attend behavioural therapy sessions.
• Rest well. Get optimum sleep.
• Exercise regularly and maintain healthy weight by following a balanced diet.
• Avoid stress by practising yoga and meditation.

The dietary restriction should be individualized as per the patient requirements.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

• Hypotension/Bradycardia

Treatment with Clonidine can cause dose-related reduce in blood pressure and heart rate Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate clonidine slowly in patient with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. In patient who have history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. Monitor blood pressure and heart rate, and adjust dosages accordingly in the patients treated concomitantly with antihypertensives or other drugs that can decreases blood pressure or heart rate or gain the risk of syncope.

• Sedation and Somnolence

Somnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled, fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day versus 4% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with Clonidine +stimulant versus 7% treated with placebo+ stimulant reported somnolence. Before using Clonidine with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with Clonidine. Advise patients to avoid use with alcohol.

• Rebound Hypertension

Abrupt discontinuation of Clonidine can cause rebound hypertension. In adults with hypertension, sudden cessation of clonidine hydrochloride extended release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety. In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptom such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. No studies evaluating abrupt discontinuation of Clonidine in children with ADHD have been conducted; however, to reduce the risk of rebound hypertension, gradually reduce the dose of Clonidine in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue Clonidine therapy without consulting their physician due to potential risk of withdrawal effects.

• Allergic Reactions

In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral Clonidine therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral Clonidine may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

• Cardiac Conduction Abnormalities

The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. There have been post-marketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring IV atropine, IV isoproterenol, and temporary cardiac pacing while taking clonidine. Titrate Clonidine slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs.

Consumption of alcohol is not recommended while receiving this medication as it may increase the risk of adverse effects and lowers the blood pressure.

Clonidine use in breast feeding patient is not recommended.

Pregnancy Category C:

Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at dose of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m² basis) produced no evidence of teratogenic or embryotoxic potential. In pregnant rats, however, dose as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in a study in which female rats were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the female rat was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study. No adequate and well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed.

• Ginseng: Clonidine is used in the treatment of hypertension. Interaction of clonidine with ginseng may affect the action of the drug as ginseng can increase the blood pressure.
• Other Herbs: Saw palmetto, hawthorn, goldenseal, ma huang, licorice and yohimbe may increase the blood pressure and interfere with the effect of clonidine.

The adverse reactions related to molecule Clonidine can be categorized as follows:

Common Adverse effects:

• Abdominal pain
• Vomiting
• Diarrhea
• Xerostomia
• Headache
• Dizziness
• Drowsiness
• Sexual dysfunction
• Itching or rash
• Stuffy nose
• Nosebleeds, etc.

Less Common adverse effect:

• Angioedema
• Depression
• Hypersensitivity
• Atrioventricular (AV) block
• Bradycardia
• Syncope
• Severe hypotension

Rare adverse effects:

• Fever
• Headache
• Fatigue
• Bradycardia
• Congestive heart failure
• Decreased sexual activity
• Thrombocytopenia
• Agitation
• Depression, etc.

The clinically relevant drug interactions of Clonidine is briefly summarized here

• Interactions with CNS-depressant Drugs

Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs.

• Interactions with Tricyclic Antidepressants

If a patient is receiving clonidine hydrochloride and also taking tricyclic antidepressants the hypotensive effects of clonidine may be reduced.

• Interactions with Drugs Known to Affect Sinus Node Function or AV Nodal Conduction

Due to a potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers).

• Use with other products containing clonidine

Do not use Clonidine concomitantly with other products containing clonidine (e.g. Catapres).

• Antihypertensive Drugs

Use caution when Clonidine is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope)

The common side of Clonidine include the following

Fatigue, Nasal Congestion, upset stomach, headache, depression, dizziness, nausea, etc.

The use of Clonidine should be prudent in the following group of special populations:

• Pregnancy

Pregnancy Category C: Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m2 basis) produced no evidence of teratogenic or embryotoxic potential. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in a study in which female rat were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the female rat was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study. No adequate and well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed.

• Nursing Mothers

Since clonidine hydrochloride is excreted in human milk, caution should be exercised when Clonidine is administered to a nursing woman.

• Pediatric Use

A study was conducted in which young rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood at doses of up to 300 mcg/kg/day, which is approximately 3 times the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis. A slight delay in onset of preputial separation was seen in males treated with the highest dose (with a no-effect dose of 100 mcg/kg/day, which is approximately equal to the MRHD), but there were no drug effects on fertility or on other measures of sexual or neurobehavioral development. Clonidine has not been studied in children with ADHD less than 6 years old.

• Patients with Renal Impairment

The impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dosage of Clonidine should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

• Adult Use in ADHD

Clonidine has not been studied in adult patients with ADHD

• Clonidine overdose: Hypertension may develop early and may be followed by Hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure.

• Manage symptomatically.

Pharmacokinetics:

• Absorption

Clonidine reaches maximum concentration in 60-90 minutes after oral administration.2 fasting status do not influence pharmacokinetics of clonidine. A 100µg oral clonidine tablet reaches a Cmax of 400.72pg/mL with an AUC of 5606.78h*pg/mL and a bioavailability of 55-87%

• Distribution

It crosses placenta and enters the breast milk and distributes readily into extravascular sites. Volume of distribution: Approx 2.9 L/kg. Plasma protein binding: 20-40%.

• Metabolism

The metabolism of clonidine is poorly understood. The main reaction in clonidine metabolism is the 4-hydroxylation of clonidine by CYP2D6, CYP1A2, CYP3A4, CYP1A1, and CYP3A5. Clonidine is <50% metabolized in the liver to inactive metabolites

• Excretion

Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces. The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h

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