Ciplar 80

Ciplar 80 contains the salt Propranolol/ Propranolol Hydrochloride 80 mg and is approved for use in the following clinical indications:

• Essential Tremors: Ciplar 80 is the only drug approved by the FDA for Essential Tremor. It is a nonselective beta-blocker that has shown tremor reduction of up to 50%. Ciplar 80 is useful in the reduction of tremor amplitude, but not frequency. Across all therapies, complete suppression of Essential Tremor is rare. Ciplar 80 appears to work best in high-amplitude, low-frequency Essential Tremors. Therapeutic doses seem to be patient-specific, and patient response is variable.
• Angina Pectoris: Ciplar 80 is helpful in the long-term therapy of angina pectoris as it works by relaxing the blood vessels and slowing the heart rate to improve the blood flow and lower blood pressure.
• Hypertension: Beta-blocking medications' antihypertensive effects still lack a precise mechanism of action. However, several potential methods have been put forth: reduced cardiac output due to competing antagonistic interactions between catecholamines at peripheral (mainly cardiac) adrenergic neuron locations; decreased sympathetic outflow to the periphery due to a significant influence; and suppression of renin activity.
• Migraine: Beta-blockers alleviate that pain by telling the blood vessels to relax so that the blood can flow normally.
• Atrial fibrillation: After coronary artery bypass surgery, beta-adrenoceptor antagonists (b-blockers) are particularly successful at preventing atrial fibrillation. Atrial fibrillation can be treated with Ciplar 80 by lowering the heart rate, allowing the heart to fully contract and relax while still being able to pump blood throughout the body efficiently. In atrial fibrillation, beta-blockers are useful for preserving sinus rhythm and regulating ventricular pace.
• Hypertrophic subaortic stenosis: A heart condition called hypertrophic subaortic stenosis, also known as hypertrophic obstructive cardiomyopathy (HOCM), is characterized by thickening of the septum, which separates the left and right sides of the heart (hypertrophic). The left ventricle's capacity to pump blood into the aorta, the body's largest artery, may be hindered by this thicker septum. In this condition, Ciplar 80 and other beta-blockers are frequently used to improve chest pain, exercise-induced shortness of breath, and the risk of irregular cardiac rhythms. It improves NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis.
• Pheochromocytoma: When combined with other drugs like alpha blockers, Ciplar 80 can help lower the high blood pressure caused by pheochromocytoma. In addition to alpha-adrenergic inhibition, Ciplar 80 is indicated to manage blood pressure and lessen the symptoms of catecholamine-secreting tumors.
• Some off-label indication for Propranolol/ Propranolol Hydrochloride includes tachyarrhythmias, treatment of restless leg syndrome, proliferating infantile hemangioma, akathisia, anxiety, and sweating.

Ciplar 80 contains the salt Propranolol/ Propranolol Hydrochloride 80 mg and is available as tablets and extended-release capsules. The method of administration of Ciplar 80 for various treatment are as follow:

• Tremors: A half to 2 tablets of Propranolol (20 mg) can be administered 30 min to 1 h before a social activity or an anxiety-provoking event, which increases tremors.
• Angina pectoris: The extended-release capsule should always be taken with or without food each time. It is typically taken before bed; take immediate-acting Propranolol tablets up to four times per day. Every day, take Propranolol around the same time(s).
• Migraine: The initial oral dose is 80 mg of Ciplar 80 once daily. The usual effective dose range is 160 to 280 mg once daily. The dosage may be increased gradually in order to achieve optimal migraine prophylaxis.
• High Blood Pressure: It can be ingested or administered intravenously by injection. The oral medication is available in both short-acting and long-acting varieties. When taken orally, Propranolol begins to show up in the blood after 30 minutes and reaches its peak effect between 60 and 90 minutes.

Ciplar 80 which contains the salt Propranolol/ Propranolol Hydrochloride 80 mg should be used in the treatment of high blood pressure, angina pectoris, migraine, and tremor along with appropriate dietary restrictions.

• High Blood Pressure: 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.
• Angina Pectoris: Avoid foods that are high in saturated fat and hydrogenated or partially hydrogenated fats. Reduce the intake of dairy products including cheese, cream, and eggs.
• Migraine: Some common triggered diets include: Baked food with yeast, such as sourdough bread, bagels, doughnuts, coffee cake, Chocolate, Cultured dairy products (like yogurt and kefir), Tomatoes, Vegetables like onions, pea pods, some beans, corn, and sauerkraut, Vinegar and Alcohol must be avoided.
• Tremors: Anything that contains caffeine, such as tea, coffee, colas, or chocolate, can temporarily worsen tremors. Some medications, including antidepressants and excessive thyroid replacement, might potentially make tremors worse.

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

• Patient who is suffering from Asthma, very slow heartbeats, or serious cardiac problem like "sick sinus" or “AV block" shouldn't use propranolol.
• Diabetes patients should not be given Ciplar 80 because it may hide some of the warning signs and symptoms of hypoglycemia (low blood sugar levels), such as palpitations and shakiness.
• The oral liquid shouldn't be administered to infants under 4.5 pounds.
• Anaphylaxis, a major allergic reaction that might be life-threatening and necessitate emergency medical intervention, may be brought on by this medication. If any experience any of the following symptoms while taking this medication: rash, itching, hoarseness, difficulty breathing, difficulty swallowing, or any swelling of the hands, face, or lips.
• In some cases, Ciplar 80 may result in heart failure, Ischemic Heart Disease.
• Angina Pectoris

Following the abrupt termination of Ciplar 80 therapy, reports of angina flare-ups and, in some cases, myocardial infarction have been made. As a result, when stopping Ciplar 80 is intended, the dosage should be decreased gradually over at least a few weeks, and the patient should be advised against stopping or interrupting medication without consulting a doctor. It is typically advised to restart Ciplar 80 therapy and take further steps necessary for the management of angina pectoris if Ciplar 80 therapy is halted and aggravation of angina develops. It may be wise to lead the following advice in individuals thought to be at risk of having occult atherosclerotic heart disease who are receiving Ciplar 80 for other purposes since coronary artery disease may go undiagnosed.

• Hypersensitivity and Skin Reaction:

Taking Ciplar 80 has been linked to hypersensitivity responses, including anaphylactic/anaphylactoid reactions.

Ciplar 80 use has been linked to cutaneous reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria.

PRECAUTIONS:

When administered to patients with impaired renal or hepatic function, Ciplar 80 should be used with caution. Hypertensive emergencies should not be treated with propranolol. Reduction of intraocular pressure can result from blocking beta-adrenergic receptors. It is important to inform patients that Ciplar 80 may affect the results of the glaucoma screening test. Redrawal could result in elevated intraocular pressure returning.

Patients who have previously experienced severe anaphylactic reactions to a variety of allergens may be more sensitive to repeated challenges while using beta-blockers, whether they are accidental, diagnostic, or therapeutic. These people might not respond to the standard epinephrine dosages used to treat allergic reactions.

The Adverse Reaction of Ciplar 80 which contains the salt Propranolol/ Propranolol Hydrochloride 80 mg for various treatment is as follow:

• Common/Serious Adverse effects of propranolol: Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type.
• Moderate Adverse effects: Lightheadedness, mental depression manifested by insomnia, lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuro psychometrics. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose-related.
• Lesser Adverse effects: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis.

Interactions with Substrates, Inhibitors, or Inducers of Cytochrome P-450 Enzymes Because propranolol's metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions.

• Substrates or Inhibitors of CYP2D6

Blood levels and/or toxicity of Ciplar 80 may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole.

• Substrates or Inhibitors of CYP1A2

Blood levels and/or toxicity of Ciplar 80 may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.

• Substrates or Inhibitors of CYP2C19

Blood levels and/or toxicity of Ciplar 80 may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole.

• Inducers of Hepatic Drug Metabolism

Blood levels of Ciplar 80 may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% of the clearance of propranolol, resulting in decreased plasma concentrations.

Cardiovascular Drugs

• Antiarrhythmics

The AUC of propafenone is increased by more than 200% by the co-administration of propranolol. The metabolism of Ciplar 80 is reduced by the co-administration of quinidine, leading to a two-threefold increased blood concentration and greater degrees of clinical beta-blockade. The metabolism of lidocaine is inhibited by the co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.

• Calcium Channel Blockers

The mean Cmax and AUC of Ciplar 80 are increased, respectively, by 50% and 30% by the co-administration of nisoldipine and by 80% and 47%, by the co-administration of nicardipine. The mean Cmax and AUC of nifedipine are increased by 64% and 79%, respectively, by co-administration of propranolol.

Ciplar 80 does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol.

Non-Cardiovascular Drugs

• Migraine Drugs:

• Administration of zolmitriptan or rizatriptan with Ciplar 80 resulted in increased concentrations of zolmitriptan (AUC increased by 56% and Cmax by 37%) or rizatriptan (the AUC and Cmax were increased by 67% and 75%, respectively).
• Theophylline

Co-administration of theophylline with Ciplar 80 decreases theophylline oral clearance by 30% to 52%.

• Benzodiazepines

Ciplar 80 can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol.

• Neuroleptic Drugs

Co-administration of long-acting Ciplar 80 at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%. Co-administration of chlorpromazine with Ciplar 80 resulted in a 70% increase in Ciplar 80 plasma level.

• Anti-Ulcer Drugs

Co-administration of Ciplar 80 with cimetidine, a non-specific CYP450 inhibitor, increased Ciplar 80 AUC and Cmax by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in Ciplar 80 concentrations. Co-administration of metoclopramide with the long-acting Ciplar 80 did not have a significant effect on propranolol's pharmacokinetics.

• Lipid Lowering Drugs

Co-administration of cholestyramine or colestipol with Ciplar 80 resulted in up to 50% decrease in Ciplar 80 concentrations. Co-administration of Ciplar 80 with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Ciplar 80 did not have an effect on the pharmacokinetics of fluvastatin.

• Warfarin

Concomitant administration of Ciplar 80 and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.

• Alcohol

Concomitant use of alcohol may increase plasma levels of propranolol.

General:

If ingestion is or may have been recent, remove gastric contents, taking care to prevent pulmonary aspiration.

Supportive Therapy:

Hypotension and bradycardia have been reported following the Ciplar 80 overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a Ciplar 80 overdose. Glucagon should be administered as 50­- 150 mcg/kg intravenously followed by a continuous drip of 1-5 mg/hour for a positive chronotropic effect. Isoproterenol, dopamine, or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. The electrocardiogram, pulse, blood pressure, neurobehavioral status, and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm.

Pharmacodynamics:

A beta-adrenergic receptor antagonist called Ciplar 80 which contains the salt Propranolol/ Propranolol Hydrochloride 80 mg is used to treat hypertension. Given once or twice daily, depending on the indication, Ciplar 80 has a long duration of action. Patients who quit taking Ciplar 80 abruptly risk worsening their angina and myocardial infarctions.

Pharmacokinetics:

PHARMACOKINETICS AND DRUG METABOLISM:

• Absorption

Ciplar 80 is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver, and on average, only about 25% of Ciplar 80 reaches the systemic circulation. Peak plasma concentration occurs about 1 to 4 hours after an oral dose. Administration of protein-rich foods increases the bioavailability of Ciplar 80 by about 50% with no change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in urine.

• Distribution

Approximately 90% of circulating Ciplar 80 is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to alpha1 glycoprotein and the R(+)-enantiomer is preferentially bound to albumin. The volume of distribution of Ciplar 80 is approximately 4 liters/kg. Ciplar 80 crosses the blood-brain barrier and the placenta and is distributed into breast milk.

• Metabolism and Elimination

Ciplar 80 is extensively metabolized, with most metabolites appearing in the urine. Ciplar 80 is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41%, and 17%, respectively, but with considerable variability between individuals. The four major metabolites are Ciplar 80 glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol. In vitro, studies have indicated that the aromatic hydroxylation of Ciplar 80 is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent, by CYP2D6. 4-hydroxy Ciplar 80 is a weak inhibitor of CYP2D6. Ciplar 80 is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-GP). Studies suggest; however, that p-GP is not dose-limiting for intestinal absorption of Ciplar 80 in the usual therapeutic dose range. In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) concerning oral clearance or elimination half-life. Partial clearance of 4-hydroxy Ciplar 80 was significantly higher and naphthyl oxyacetic acid was significantly lower in EMs than in PMs. The plasma half-life of Ciplar 80 is from 3 to 6 hours.