Naproxen Sodium

Naproxen Sodium

275mg Tablet

550mg Tablet

Drug Category: Non-steroidal Anti-inflammatory / Analgesic

Brand Name: Flanax

Drug Description:

Naproxen Sodium is a non-steroidal agent developed by Syntex Research. It is non-narcotic analgesic agent with marked anti-inflammatory actions. It has demonstrated these properties in human clinical studies and classical animal test systems. It exhibits its anti-inflammatory effect even in adrenalectomized animals, indicating that its action is not mediated through the pituitary-adrenal axis. It inhibits prostaglandin synthetase, as do no other non-steroidal analgesic/anti-inflammatory agents. As with other agents, however, the exact mechanism of its anti-inflammatory and analgesic actions is not known.

Naproxen Sodium is not a CNS depressant and does not induce metabolizing enzymes.

Naproxen Sodium is freely soluble in water and is rapidly and completely absorbed from the gastrointestinal tract after oral administration. Because of this rapid and complete absorption, significant plasma levels and onset of pain relief are obtained in patients within 20 minutes of administration. It has a mean biological half-life of approximately 13 hours. At therapeutic levels it is greater than 99% bound to serum albumin.

Approximately 95% of a Naproxen Sodium dose is excreted in the urine as unchanged naproxen, 6-0-desmethylnaproxen and their conjugates. The rate of excretion has been found to coincide closely with the rate of drug disappearance from the plasma.

Indications:

Naproxen Sodium is indicated in the relief of mild to moderately severe pain with or without accompanied inflammation, such as musculoskeletal trauma, post-operative pain and post-dental extraction. It is also indicated for the relief of pain associated with post-partum cramping and dysmenorrhea.

Dosage and Administrations:

In the treatment of rheumatic disorders, the usual dose is 550mg to 1100mg (1-2 tablets) as a single dose or in 2 divided doses.

In other painful conditions (such as dysmenorrhea and acute musculoskeletal disorders), the usual initial dose is 550mg (1 tablet) followed by 275mg every 6 to 8 hours, up to a maximum daily dose of 1375mg after the first day.

In acute gout, an initial dose of 825mg followed by 275mg every 8 hours.

For migraine, 825mg is given and may be followed by 275mg to 550mg after at least half an hour, to a maximum daily dose of 1375mg.

Or as prescribed by a physician.

Warning:

Naproxen Sodium is not to be given to patients who have a history of:

• Stroke (Cerebrovascular Accident)
• Heart attack (Myocardial Infarction)
• Coronary artery bypass graft
• Uncontrolled hypertension
• Congestive heart failure (NYHA II-IV)

Other Contraindications:

It is contraindicated in patients with history of hypersensitivity to aspirin of any other NSAIDs. It is also contraindicated in patients with previous or active peptic ulceration. Naproxen Sodium should be used with caution in patients with cardiac, liver, and renal disease. Dose should be adjusted accordingly and renal and liver functions should be constantly monitored when taking the drug.

Use in patients with impaired renal function:

As Naproxen and its metabolites are eliminated to a large extent (95%) by urinary excretion via glomerular filtration, Naproxen Sodium should be used with great caution in patients with significantly impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients.

Naproxen Sodium should not be used chronically in patients having baseline creatinine clearance less than 20ml/minute.

Certain patients, specifically those where renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure, and pre-existing renal disease. Should have renal function assessed before and during Naproxen Sodium therapy. Some elderly in whom impaired renal function may be expected could also fall within this category. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of Naproxen metabolites in these patients.

Use in patients with impaired liver function:

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for Naproxen Sodium dosing is unknown, but its is prudent to use the lowest effective dose.

Use in the elderly:

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The implication of this finding for Naproxen Sodium dosing is unknown. As with other drugs in the elderly, it is prudent to use the lowest effective dose.

Interactions with other drugs:

Due to the high plasma protein binding of naproxen, patients simultaneously receiving hydantoins should be closely monitored for adjustment of dose if required. Interactions have not been observed in clinical studies with Naproxen Sodium and anti-coagulants or sulfonylureas, but caution is advised, nonetheless, since interaction has been seen with other non-steroidal agents of this class.

The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class. Inhibition of renal lithium clearance leading to an increase in plasma lithium concentration has been reported also.

Naproxen Sodium and other non-steroidal anti-inflammatory drugs can reduce the anti-hypertensive effect of propranolol and other beta-blockers.

Probenecid given concurrently increases naproxen plasma levels and extends its plasma half-life significantly.

Concomitant administration of Naproxen Sodium and methotrexate should be with caution, because Naproxen has been reported among other non-steroidal anti-inflammatory drugs to reduce the tubular secretion of methotrexate in an animal model, and thus possibly enhance its toxicity.

It is suggested that Naproxen Sodium therapy be temporarily discontinued 48 hours before adrenal function tests are performed, because it may artificially interfere with some tests for 17-ketogenic steroids. Similarly it may interfere with some urinary assays of 5-hydroxyindoleacetic acid.

Adverse Reactions:

Most commonly reported adverse events: abdominal discomfort, epigastric distress, headache, nausea, peripheral edema (mild), tinnitus, and vertigo.

The following adverse events are rate but have been reported: alopecia, anaphylactic reactions to naproxen and Naproxen Sodium formulation, angioedema, aplastic and hemolytic anemia, cognitive dysfunction, eosinophilic pneumonitis, epidermal necrolysis, erythema multiforme, fatal hepatitis, gastrointestinal bleeding and/or perforation, granulocytopenia, hearing impairment, hematuria, inability to concentrate, insomnia, jaundice, nephropathy, peptic ulceration, photosensitive dermatitis, skin rash, Stevens-Johnson syndrome, thrombocytopenia, ulcerative stomatitis, vaculitis, and visual disturbances.

Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking Naproxen Sodium.

Use in Pregnancy:

As with other drugs of this type, Naproxen Sodium produces a delay in parturition in animals and also affects the human fetal cardiovascular system (closure of the ductus arteriosus). Therefore it should not be used during pregnancy unless clearly needed. The use of Naproxen Sodium in pregnancy requires cautious of possible benefits against potential risks to the mother and fetus, especially in the first and third trimesters.

Naproxen has been found in the milk of lactating mothers. The use of Naproxen Sodium should therefore be avoided in patients who are breast feeding.

Overdosage:

Significant overdosage of the drug may be characterized by drowsiness, heart burn, indigestion, nausea or vomiting. No evidence of toxicity or late sequelae had been reported 5 – 15 months after ingestion, for three to seven days, of doses up to 3.3g/day. One patient ingested a single dose equivalent to 27.5g of Naproxen Sodium and experienced mild nausea and indigestion. It is not known what dose of the drug would be life threatening.

Should a patient ingest a large quantity of Naproxen Sodium accidentally or purposefully, the stomach may be emptied and usual supportive measures employed. Animal studies indicate that the prompt administration of activated charcoal in adequate amounts would tend to reduce markedly the absorption of the drug.

Storage Condition:

Store at temperature not exceeding 30^oC. Protect from heat.

Butorphanol Tartrate

Butorphanol Tartrate

2mg/ml Solution for Injection (I.M. / I.V.)

Drug Category: Opioid Analgesic

Brand Name: Ziphanol

Description:

Brown clean ampule containing colorless solution.

Indications:

Butorphanol is used to relief of moderate to severe pain, for preoperative or pre-anesthetic medication as a supplement to balanced anesthesia, for relief of pain during labor.

Dosage and Administration:

Butorphanol has a factors to be considered in determining the dose are age, body-weight, physical status, underlying pathological conditions, use of other drugs, type of anesthesia to be used, and surgical procedure involved. Use in the elderly, in patients with hepatic or renal disease, or in labor requires extra caution. The following doses are for patients who do not have impaired hepatic or renal function and who are not on CNS active agents

1. Pain

• Intravenous: The usual recommended single dose for IV administration is 1mg repeated every 3 to 4 hours as necessary. The effective dosage range, depending on the severity of pain, is 0.5 to 2 mg repeated every 3 to 4 hours.
• Intramuscular: The usual recommended single dose for IM administration is 2mg in patients who will be able to remain recumbent, in the event drowsiness or dizziness occurs. This may be repeated every 3 to 4 hours, as necessary. The effective dosage range depending on the severity of pain is 1 to 4mg repeated every 3 to 4 hours. There are insufficient clinical data to recommend single doses above 4mg.
• Both expected efficacy and adverse reaction should be considered in dosage adjustment. The dose of this drug recommended for elderly patients, patients with hepatic or renal impairment should generally be half the recommended adult dose (0.5mg IV and 1.0mg IM). Repeat doses should be determined by the patient's response rather than at fixed intervals, but will generally be no less than 6 hours apart.

2. Use as Preoperative/Pre-anesthetic Medications
   The preoperative medication dosage should be individualized. The usual adult dose is 2mg IM, administered 60 – 90 minutes before surgery. This is approximately equivalent in sedative effect to 10mg morphine or 80mg meperidine.
3. Use in Balance Anesthesia
   The usual dose is 2mg IV shortly before induction and/or 0.5 to 1.0mg IV in increments during anesthesia. The increment may be higher, up to 0.06mg/kg (4mg/70kg), depending on previous sedative, analgesic, and hypnotic drugs administered. The total dose of this drug will vary; however, patients seldom requires less than 4mg or more than 12.5mg (approximately 0.06 to 0.18mg/kg).
   Opioid, including this drug, may not produce appropriate analgesic effect for every patients or every state during surgery. Analgesic fail during increased, intensive inhalation anesthetic or another IV should be considered.
4. Labor
   In patients at full term or without fetal distress in early labor a 1-2mg dose IV or IM may be administered and repeated after 4 hours. Alternative analgesic should be used for pain associated with delivery is expected to occur within 4hours. Other analgesics should be used when delivery is expected within 4 hours. Dosage titration should be based on concurrent analgesics, sedatives, expected time of delivery and response of the first administration. If concomitant use of this drug with drugs that may potentiate its effects effect is deemed necessary, the lowest effective dose should be employed.

Adverse Reactions:

1. The most frequently reported adverse experiences across all clinical trials with this drug were somnolence (43%), dizziness (19%0), nausea and/or vomiting (13%).
2. The following adverse experiences were reported at a frequency of 1% or greater in clinical trials.

• Body as a Whole: asthenia/lethargy, headache, sensation of heat.
• Digestive: dry mouth, nausea and or vomiting, stomach pain.
• Nervous: anxiety, confusion, dizziness, euphoria, floating feeling nervousness, paresthesia, somnolence.
• Skin and Appendages: sweating/clammy, pruritus.
• Special Senses: blurred vision

3. The following adverse experiences were reported with a frequency of less than 1% in clinical trials

• Cardiovascular: hypotension, syncope.
• Nervous: abnormal dreams, agitation, dysphoria, hallucination, hostility
• Skin and Appendages: rash/hives.
• Urogenital: impaired urination.

Contraindications:

Butorphanol is not recommended for use in patients dependent on narcotics. Such patients should have an adequate period of withdrawal from opioid drugs prior to beginning butorphanol therapy. In patients taking opioid analgesics chronically, butorphanol has precipitated withdrawal symptoms such as anxiety, agitation, mood changes, hallucination, dysphoria, weakness, and diarrhea, because of its opioid antagonist properties.

This drug should be carefully administered to the following patients.

1. Because of the difficulty in assessing opioid tolerance in patients who have recently received repeated doses of narcotic analgesic medication, caution should be used in the administration of butorphanol to such patients.
2. Head Injury and Increased Intracranial Pressure
   As with opioids, the use of butorphanol in patients with head injury may be associated with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, drug-induced miosis, and alterations in mental state that would obscure the interpretation of the clinical course of patients with head injuries. In such patients, butorphanol should be used only if the benefits of use outweigh the potential risks.
3. Disorders of Respiratory Function or Control
   Butorphanol may produce respiratory depression, especially in patients receiving other CNS active agents, or patients suffering from CNS disease or respiratory impairment.
4. Cardiovascular Effects
   Because butorphanol may increase the work of the heart, especially the pulmonary circuit, the use of butorphanol in patients with acute myocardial infarction, ventricular dysfunction, or coronary insufficiency should be limited to those situations where the benefits clearly outweigh the risk. Severe hypertension has been reported rarely during butorphanol therapy. In such cases, butorphanol should be discontinued and the hypertension treated with anti-hypertensive drugs. In patients who are not opioid dependent, naloxone has also been reported to be effective.

Precautions:

Warning

When ampules are cut, glass particles can mixed with drug solution. Therefore caution should be taken to prevent from mixing. In particular, caution should be taken when its is used by elderly or children.

General caution

1. Effects such as drowsiness or dizziness impair the mental and physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery.
2. Alcohol should not be consumed while using butorphanol.
3. Drugs having antagonistic action and effect of opioid, less frequent than morphine but can be abused. Due to prolonged use of this drug, light withdrawal symptoms, excessive use and addition have been reported. Special care should be exercised in administering butorphanol to patients with a history of drug abuse or to patients receiving the drug on a continuous bases for an extended period.
4. Use for outpatients
   Drowsiness and dizziness may occur. Caution should be taken until individual characteristic response to this drug is obtained.

Drug Interaction:

Concurrent use of butorphanol with central nervous system depressants (eg. Alcohol, barbiturates, tranquilizers, and antihistamines) may result in increased central nervous system depressant effects. When use concurrently with such drugs, the dose of butorphanol should be the smallest effective dose and the frequency of dosing reduced as much as possible when administered concomitantly with drugs that potentiate the action of opioids.

It is known if the effects of butorphanol are altered by other concomitant medications that affect hepatic metabolism of drugs (cimetidine, erythromycin, theophylline, etc), but physicians should be alert to the possibility that a smaller initial dose and longer intervals between doses may be needed.

NO information is available about the use of butorphanol concurrently with MAO inhibitors.

Pregnancy, Nursing mothers and Geriatric Use

1. Pregnancy
   Reproduction studies in mice, rats and rabbits during organogenesis did not reveal any teratogenic potential to butorphanol. However, pregnant rats treated subcutaneously with butorphanol at 1mg/kg (5.9mg/m2) had a higher frequency of stillbirths than controls. Butorphanol at 30mg/kg/oral (360mg/m2) and 60mg/kg/oral (720mg/m2) also showed higher incidences of post- implantation loss in rabbits. There are no adequate and well-controlled studies of this drug in pregnant women before 37 weeks of gestation. This drug should be use during pregnancy only if potential benefit justifies the potential risk to the infant.
2. Labor and Delivery
   There have been rare reports of infant respiratory distress/apnea following the administration of this drug during labor. The reports of respiratory distress/apnea have been associated with administration of a dose within 2 hours of delivery, use of multiple doses, use with additional analgesic or sedative drugs, or use in preterm pregnancies.
   In a study of 119 patients, the IV administration of 1mg of this drug during labor was associated with transient sinusoidal fetal heart rate patterns, but was not associated with adverse neonatal outcomes. In the presence of an abnormal fetal heart rate pattern, this drug should be used with caution.

3. Nursing mothers
   Butorphanol has been detected in milk following administration of this drug to nursing mothers. The amount an infant would receive is probably clinically insignificant (estimated 4mcg/L of milk in a mother receiving 2mg IM four times a day).
4. Geriatrics use
   Due to changes in clearance, the mean half-life of butorphanol is increased by 25% (to over 6hours) in patients over the age of 65 years. Elderly patients may be more sensitive to the side effects of butorphanol.
5. Others
   Butorphanol is not recommended for use in patients below 18 years of age because safety and efficacy have not been established in this population.

Overdosage:

The clinical manifestations of butorphanol overdose are those of opioid drugs in general. The most serious symptoms are hypoventilation, cardiovascular insufficiency, coma, and death.

The management of suspected butorphanol overdosage includes maintenance of adequate ventilation, peripheral perfusion, normal body temperature, and protection of the airway. Patients should be under continuous observation with adequate serial measure of mental state, responsiveness, and vital signs. Oxygen and ventilatory assistance should be available with continual monitoring by pulse oximety if indicated. In the presence of coma, placement of an artificial airway may be required. An adequately intravenous portal should be maintained to facilitate treatment of hypotension associated with vasodilation.

The use of specific opioid antagonist such as naloxone should be considered. As the duration of butorphanol action usually exceeds the duration of action of naloxone, repeated dosing with naloxone may be required.

In managing cases of suspected butorphanol overdosage, the possibility of multiple drug ingestion should always be considered.

Others (Carcinogenesis, Mutagenesis, Impairment of Fertility)

There was no evidence of carcinogenicity for this drug.

Butorphanol was not genotoxic in S. typhimurium or E. coli assays or in unschedules DNA synthesis and repair assays conducted in cultured human fibroblast cells.

Rats treated orally with 160mg/kg/day (955mg/m2) had reduced pregnancy rate. However, a similar effect was not observed with 2.5mg/kg/day (14.75mg/m2) subcutaneous dose.

Storage Condition:

Store at temperatures not exceeding 30^oC.

Keep medicine out of children's reach.

Clonidine HCl

Clonidine HCl

75mcg Tablet

150mcg Tablet

150mcg Ampule

Drug Category: Anti-hypertensive Drug

Brand Name: Catapres®

Indications:

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.

Tablets

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).

Ampules

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..

Contraindications:

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 2^nd and 3^rd 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.

Interactions:

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

Pregnancy

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.

Lactation

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.

Fertility

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

gynecomastia

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

Investigations

blood glucose increase

Overdosage:

Symptoms

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.

Treatments

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.

Pharmacokinetics:

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.

Metabolism

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.

Toxicology:

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 30^oC.

Telmisartan

Telmisartan

40mg Tablet

80mg Tablet

Drug Category: Anti-hypertensive drug

Indications:

Treatment of essential hypertension. Prevention of cardiovascular morbidity and mortality in patients 55 years or older at high risk of cardiovascular disease (see Pharmacological properties).

Dosage and Administration:

Adults

Treatment of essential hypertension

The recommended dose is 40mg once daily. Some patients may already benefit at a daily dose of 20mg. In cases where the target blood pressure is not achieved, telmisartan dose can be increased to maximum of 80mg once daily. Alternatively, telmisartan may be used in combination with thiazide-type diuretics such as hydrochlorothiazide, which has been shown to have an additive blood pressure lowering effect with telmisartan. When considering raising the dose, it must be borne in mind that the maximum anti-hypertensive effect is generally attained four – eight weeks after the start of treatment. In patients with sever hypertension treatment with telmisartan at doses up to 160mg alone and in combination with hydrochlorothiazide 12.5 – 25mg daily was well tolerated and effective.

Prevention of cardiovascular morbidity and mortality

The recommended dose is 80mg once daily. It is not known whether doses lover than 80mg of telmisartan are effective in preventing cardiovascular morbidity and mortality.

When initiating telmisartan therapy for the prevention of cardiovascular morbidity and mortality, monitoring adjustment of medications that lover blood pressure may be necessary. Telmisartan may be taken with or without food.

Renal impairment

No posology adjustment is required for patients with renal impairment, including those on hemodialysis. Telmisartan is not removed from blood by hemofiltration.

Hepatic impairment

In patients with mild to moderate hepatic impairment the posology should not exceed 40mg once daily.

Elderly

No dosing adjustment is necessary.

Children and adolescents

The safety and efficacy of telmisartan for use in children below 18 years have not been established.

Contraindications:

• Hypersensitivity to the active ingredient or any of the excipients
• Second and third trimesters of pregnancy
• Lactation
• Biliary obstruction disorders
• Severe hepatic impairment

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

Special warnings and precautions:

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy.

Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and if appropriate, alternative therapy should be started.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplant

When telmisartan is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of telmisartan in patients with a recent kidney transplant.

Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhea or vomiting. Such conditions, especially volume and/or sodium depletion, should be corrected before the administration of telmisartan.

Dual blockade of the renin-angiotensin-aldosterone system

As a consequence of inhibiting renin-angiotensin-aldosterone system changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system. Dual blockade of the renin-angiotensin-aldosterone system (e.g. by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should therefore be limited to individually defined cases with close monitoring of renal function.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of renin-angiotensin system. Therefore, the use of telmisartan is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering form aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Hyperkalemia

During treatment with medicinal products that affect the renin-angiotensin-aldosterone system hyperkalemia may occur, especially in the presence of renal impairment and/or heart failure. Monitoring of serum potassium in patients at risk is recommended.

Based on experience with the use of medicinal products that affect the renin-angiotensin system, concomitant use with potassium-sparing diuretics, potassium supplements, salts substitute containing potassium or other medicinal products that may increase the potassium level (heparin, etc.) may lead to an increase in serum potassium and should therefore be co-administered cautiously with telmisartan.

Hepatic impairment

Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduce clearance. Telmisartan should be used with caution in these patients.

Sorbitol

This product contains 338mg of sorbitol per maximum recommended daily dose. Patients with the rare hereditary condition of fructose intolerance should not take this medicine.

Other

As observed for angiotensin converting enzyme inhibitors, angiotensin receptor blockers including telmisartan are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

As with any anti-hypertensive agent, excessive reduction of blood pressure in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in a myocardial infarction or stroke.

Interactions:

Telmisartan may increase the hypotensive effect of other anti-hypertensive agents. Other interactions of clinical significance have not been identified.

Co-administration of telmisartan did not result in a clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine. For digoxin a 20% increase in median plasma digoxin trough concentration has been observed (39% in a single case), monitoring of plasma digoxin levels should be considered.

In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC_0-24 and C_max of ramipril and ramiprilat. The clinical relevance of this observation is not known.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors.

Cases have also been reported with angiotensin II receptor antagonists including telmisartan.Therefore, serum lithium level monitoring is advisable during concomitant use.

Treatments with NSAIDs (i.e. ASA at anti-inflammatory dosage regimens, COX-2 inhibitors and not-selective NSAIDs) is associated with the potential for acute renal insufficiency in patients who are dehydrated. Compounds acting on the renin-angiotensin-system like telmisartan may have synergistic effects. Patients receiving NSAIDs and telmisartan should be adequately hydrated and be monitored for renal function at the beginning of combined treatment.

A reduced effect of anti-hypertensive drugs like telmisartan by inhibition of vasodilating prostaglandins has been reported during combined treatment with NSAIDs.

Fertility, pregnancy and lactation:

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy.

The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy.

Preclinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity.

Angiotensin II receptor antagonists exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension.

Telmisartan is contraindicated during lactation since it is not known whether it is excreted in human milk. Animal studies have shown excretion of telmisartan in breast milk.

Fertility

No studies on fertility in humans have been performed. In preclinical studies, an effect of telmisartan on male and female fertility was not observed.

Effects on ability to drive and use machines:

No studies on the effect on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it should be taken into account that dizziness or drowsiness may occasionally occur when taking anti-hypertensive therapy.

Side effects:

The overall incidence of adverse events reported with telmisartan (41.4%) was usually comparable to placebo (43.9%) in controlled clinical trials in patients treated for hypertension. The incidence of adverse events was not dose related and showed no correlation with gender, age or race of the patients.

The safety profile of telmisartan in patients treated for prevention of cardiovascular morbidity and mortality was consistent with that obtained in hypertensive patients.

The adverse drug reactions listed below have been accumulated from controlled clinical trials in patients treated for hypertension and from post-marketing reports. The listing also takes into account serious adverse events and adverse events leading to discontinuation reported in three clinical long-term studies including 21642 patients treated with telmisartan for prevention of cardiovascular morbidity and mortality for up to six years.

Infections and infestation:

Urinary tract infections (including cystitis), upper respiratory tract infections, sepsis included fatal outcome

Blood and lymphatic system disorders:

Anemia, eosinophilia, thrombocytopenia

Immune system disorders:

Anphylactice reaction, hypersensitivity

Metabolism and nutrition disorders:

Hyperkalemia, hypoglycemia (in diabetic patients)

Psychiatric disorders:

Anxiety, insomnia, depression

Nervous system disorders:

Syncope (faint)

Eye disorders:

Visual disturbance

Ear and labyrinth disorders:

Vertigo

Cardiac disorders:

Bradycardia, tachycardia

Vascular disorders:

Hypotension, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders:

Dyspnea

Gastrointestinal disorders:

Abdominal pain, diarrhea, dry mouth, dyspepsia, flatulence, stomach discomfort, vomiting

Hepatobiliary disorders:

Hepatic function abnormal / liver disorder*

*Most cases of hepatic function abnormal / liver disorder from post-marketing experience with telmisartan occurred in patients in Japan, who are more likely to experience these adverse reactions.

Skin and subcutaneous tissue disorders:

Pruritus, hyperhidrosis, rash, angioedema (with fatal outcome), eczema, erythema, urticaria, drug eruption, toxic skin eruption

Musculoskeletal, connective tissue and bone disorders:

Arthralgia, back pain, muscle spasms (cramps in legs) pain in extremity (leg pain), myalgia, tendon pain (tendinitis like symptoms)

Renal and urinary tract disorders:

Renal impairment including acute renal failure

(see also under Special precautions and warnings)

General disorders and administration site conditions:

Chest pain, influenza-like illness, asthenia (weakness)

Investigations:

Hemoglobin decreased, blood uric acid increased, blood creatinine increased, hepatic enzymes increased, blood creatine phosphokinase (CPK) increased.

Overdose:

Limited information is available with regard to overdose in humans. The most prominent manifestations of telmisartan overdose were hypotension and tachycardia, bradycardia also occurred. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

Pharmacological properties:

Telmisartan is an orally effective and specific angiotensin II receptor (type AT₁) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT₁ receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT₁ receptor. Telmisartan selectively binds the AT₁ receptor. The binding is long lasting. Telmisartan does not show affinity for other receptors, including AT₂ and other less characterized AT receptors. The functional role of these receptors is not known, nor is the effect of their possible over-stimulation by telmisartan. Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse effects.

In man, an 80mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.

Treatment of essential hypertension

After the first dose of telmisartan, the anti-hypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 weeks after the start of treatment and is sustained during long-term therapy.

The anti-hypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the nest dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of 40 and 80 mg of telmisartan in placebo controlled clinical studies.

There is an apparent trend to a dose relationship to a time to recovery of baseline SBP. In this respective data concerning DBP are inconsistent.

In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The anti-hypertensive efficacy of telmisartan has been compared to anti-hypertensive drugs such as amlodipine, atenolol, enalapril, hydrochlorothiaze, losartan, lisinopril, ramipril and valsartan.

Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.

Telmisartan treatment has been shown in clinical trials to be associated with statistically significant reductions in Left Ventricular Mass and Left Ventricular Mass Index in patients with hypertension and Left Ventricular Hypertrophy.

Telmisartan treatment has been shown in clinical trials (including comparators like losartan, ramipril and valsartan) to be associated with statistically significant reductions in proteinuria (including microalbuminuria and macroalbuminuria) in patients with hypertension and diabetic nephropathy.

The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin converting enzyme inhibitors in clinical trails directly comparing the two anti-hypertensive treatments.

Prevention of cardiovascular morbidity and mortality

ONTARGET (ONgoin Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial)

compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril on cardiovascular outcomes in 25620 patients aged 55 years or older with history of coronary artery disease, stroke, peripheral vascular disease, or diabetes mellitus accompanied by evidence of end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which represents a broad cross-section of cardiovascular high risk patients.

Patients were randomized to one of the three following treatment groups: telmisartan 80mg (n=8542), ramipril 10mg (n=8576), or the combination of telmisartan 80mg plus ramipril 10mg (n=8502), and followed for a mean observation time of 4.5 years. The population studied was 73% male, 74% Caucasian, 14% Asian and 43% were 65 years of age or older. Hypertension was present in nearly 83% of randomized patients: 69% of patients had a history of hypertension at randomization and an additional 14% had actual blood pressure readings above 140/90mmHg. At baseline, the total percentage of patients with a medical history of diabetes was 38% and an additional 3% presented with elevated fasting plasma glucose levels. Baseline therapy included acetylsalicylic acid (76%), statins (62%), beta-blockers (57%), calcium channel blockers (34%), nitrates (29%) and diuretics (28%).

The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure.

Adherence to treatment was better for telmisartan than for ramipril or the combination of telmisartan and ramipril, although the study population had been pre-screened for tolerance to treatment with an ACE-inhibitor. The analysis of adverse events leading to permanent treatment discontinuation and of serious adverse events showed that cough and angioedema were less frequently reported in patients treated with telmisartan than in patients treated with ramipril, whereas hypotension was more frequently reported with telmisartan.

Telmisartan has similar efficacy to ramipril in reducing the primary endpoint. The incidence of the primary endpoint was similar in the telmisartan (16.7%), ramipril (16.5%) and telmisartan plus ramipril combination (16.3%) arms.

The hazard ration for telmisartan vs. ramipril was 1.01 (97.5% CI 0.93 – 1.10, p (non-inferiority) = 0.0019). The treatment effect was found to persist following corrections for difference in systolic blood pressure at baseline and over time. There was no difference in the primary endpoint based on age, gender, race, baseline therapies or underlying disease.

Telmisartan was also found to e similarly effective to ramipril in several pre-specified secondary endpoints, including a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, the primary endpoint in the reference study HOPE (The Heart Outcomes Prevention Evaluation Study), which has investigated the effect of ramipril vs. placebo. The hazard ratio of telmisartan vs. ramipril for this endpoint in ONTARGET was 0.99 (97.5% CI 0.90 – 1.08, p (non-inferiority) = 0.0004).

Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone. In addition, there was a significantly higher incidence of hyperkalemia, renal failure, hypotension and syncope in the combination arm. Therefore the use of a combination of telmisartan and ramipril is not recommended in this population.

Pediatric population

The blood pressure lowering effects of two doses of telmisartan were assessed in hypertensive patients aged 6 to <18 years (n=76) after taking telmisartan 1mg/kg (n=30 treated) or 2mg/kg (31 treated) over four-week treatment period. After adjustment for age group effects and baseline SBP values an average placebo-corrected SBP change from baseline (primary objective) of 8.5mmHg was observed in the telmisartan 2mg/kg group, and a -3.6mmHg SBP change was found in the telmisartan 1mg/kg group. The adjusted and placebo-corrected DBP changes from baseline were 4.5mmHg and -4.8mmHg in the telmisartan 1mg/kg and 2mg/kg groups, respectively. The change was dose dependent. The safety profile appeared generally comparable to that observed in adults.

Pharmacokinetics:

Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for telmisartan is about 50%.

When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC) of telmisartan varies from approximately 6% (40mg dose) to approximately 19% (160mg dose). By 3 hours after administration plasma concentrations are similar whether telmisartan is taken fasting or with food.

The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy.

Gender differences in plasma concentration were observed, C_max and AUC being approximately 3-and 2-fold higher, respectively, in females compared to males without relevant influence of efficacy. Telmisartan is largely bound to plasma protein (>99.5%), mainly albumin and alpha-1 glycoprotein. The mean steady state apparent volume of distribution (V_SS) I approximately 500L.

Telmisartan is metabolized by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.

Telmisartan is characterized by biexponential decay pharmacokinetics with a terminal elimination half-life of >20hours. The maximum plasma concentration (C_max) and, to a smaller extent, area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan.

After oral (and intravenous) administration telmisartan is nearly exclusively excreted with the feces, exclusively as unchanged compound. Cumulative urinary excretion is <2% of dose.

Total plasma clearance (Cl_tot) is high (approximately 900ml/min compared with hepatic blood flow (about 1500mg/min)

Elderly patients

The pharmacokinetics of telmisartan do not differ between younger and elderly patients.

Patients with renal impairment

Lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.

Patients with hepatic impairment

Pharmacokinetics studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%. The elimination half-life is not changed in patients with hepatic impairment.

Pediatric population

The pharmacokinetics of two doses of telmisartan were assessed as a secondary objective in hypertensive patients (n=57) aged 6 to <18 years after taking telmisartan 1mg/kg or 2mg/kg over a four-week treatment period. Pharmacokinetic objectives included the determination of the steady-state of telmisartan in children and adolescents, and investigation of age-related differences. Although the study was too small for a meaningful assessment of the pharmacokinetics of children under 12 years of age, the results are generally consistent with the finding in adults and confirm the non-linearity of telmisartan, particularly for C_max.

Toxicology:

In preclinical safety studies doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters (erythrocytes, hemoglobin, hematocrit) and changes in renal hemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassium in normotensive animals. In dogs renal tubular dilation and atrophy were observed. Gastric mucosal injury (erosion, ulcers or inflammation) also was noted in rats and dogs. These pharmacologically mediated side effects, known from preclinical studies with both angiotensin converting enzyme inhibitors and angiotensin II antagonists, were prevented by oral saline supplementation.

In both species increase plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of ACE-inhibitors and other angiotensin II antagonists, do not appear to have clinical significance.

Animal studies indicated some hazardous potential of telmisartan to the postnatal development of the offspring: lower body-weight, delayed eye opening, higher mortality.

There was no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice.

Storage Condition:

Store at temperature not exceeding 30^oC.