1. ACTOS HISTORY
How was Actos discovered?

Actos is a product of Takeda Pharmaceuticals.

The US FDA approved Actos on 16th July 1999. 

The Company was incorporated as Chobei Takeda & Co., Ltd., with capital of 5.3 million yen and Chobei Takeda V as president. The Company went from being an individually owned business to a modern corporate organization integrating R&D, manufacturing and marketing. The Company changed its name to Takeda Pharmaceutical Industries, Ltd. in 1943 (its English name was changed to Takeda Chemical Industries, Ltd. in 1961). Around this time, Takeda began introducing a succession of its own products. Among these were Calmotin (a sedative), Lodinon (an injectable form of D-glucose) and Novoroform (an analgesic). Takeda steadily expanded its pharmaceutical business and even began exports to the U.S., Russia and China.

Outside Japan, Takeda has subsidiaries and affiliates in the U.S., Europe and Asia. These include development, production, and sales and marketing companies as well as holding companies in the U.S. and Europe.

Note: World-drugs.net sells generic version of Actos

2.ACTOS FACTS

Actos is an anti-diabetic drug from the thiazolidinedione class.

Like other thiazolidinediones, its mechanism of action is by activation of the intracellular receptor class of the peroxisome proliferator-activated receptors (PPARs), specifically PPAR?.

Actos is a pure ligand of PPAR?, and has no PPARa-binding action. Apart from its effect on insulin resistance, it appears to have an anti-inflammatory effect: nuclear factor kappa-B (NFaB) levels fall and inhibitor (IaB) levels increase in patients on Actos. 

 

3.ABOUT ACTOS MEDICATION

What is Diabetes and what are its causes
Diabetes (diabetes mellitus): a condition characterized by hyperglycemia resulting from the body's inability to use blood glucose for energy. In type 1 diabetes, the pancreas no longer makes insulin and therefore blood glucose cannot enter the cells to be used for energy. In type 2 diabetes, either the pancreas does not make enough insulin or the body is unable to use insulin correctly.

Pre-diabetes: a condition in which blood glucose levels are higher than normal but are not high enough for a diagnosis of diabetes. People with pre-diabetes are at increased risk for developing Type 2 diabetes and for heart disease and stroke. Other names for pre-diabetes are impaired glucose tolerance and impaired fasting glucose.

Type 1 diabetes: a condition characterized by high blood glucose levels caused by a total lack of insulin. Occurs when the body's immune system attacks the insulin-producing beta cells in the pancreas and destroys them. The pancreas then produces little or no insulin. Type 1 diabetes develops most often in young people but can appear in adults.

Type 2 diabetes: a condition characterized by high blood glucose levels caused by either a lack of insulin or the body's inability to use insulin efficiently. Type 2 diabetes develops most often in middle-aged and older adults but can appear in young people.

Other causes of diabetes

There are some other causes of Diabetes, including certain diseases of the pancreas, but they are all very rare. Sometimes an accident or an illness may reveal Diabetes if it is already there, but they do not cause it.

What are the symptoms of Diabetes?

The main symptoms of Diabetes are:

• increased thirst
• going to the loo all the time – especially at night
• extreme tiredness
• weight loss
• genital itching or regular episodes of thrush
• blurred vision.

Type 2 diabetes develops slowly and the symptoms are usually less severe. Some people may not notice any symptoms at all and their Diabetes is only picked up in a routine medical check up. Some people may put the symptoms down to 'getting older' or 'overwork'.

Type 1 diabetes develops much more quickly, usually over a few weeks, and symptoms are normally very obvious.

In both types of Diabetes, the symptoms are quickly relieved once the Diabetes is treated. Early treatment will also reduce the chances of developing serious health problems.

What are the risk factors for Diabetes?

•  Age :
All people are vulnerable to the disease throughout their lives. However, the risk is higheras you grow older. There is a gradual increase in susceptibility, with slight peaks at puberty and during pregnancy, until we reach the age of 40. Then there is a rapid jump.

•  Heredity
If you have a family history of Diabetes, especially parents or siblings with Diabetes, then you're near the top of the list in terms of risk. Heredity is the most important predisposing factor for Diabetes, especially for type-I diabetes.

Type- II diabetes also tends to run in families, but since 80 to 85 percent of all cases occur among people who are over 40 and overweight, obesity is considered more important in the development of this form of the disease.

•  Obesity
80 to 85 percent of people with type-II diabetes are overweight. It is true that not all overweight people have Diabetes. But if you are obese, you may be setting yourself up for this disease 10 or 20 years from now. (You are considered obese, if you are more than 20 percent over ideal body weight.)

•  Race
In the United States the disease is more common among African-Americans, Hispanics and American Indians. More than 40% of Pima Indians in the United States have Type 2 diabetes. However, that race alone does not predict Diabetes; it must be combined with another factor, such as obesity.

•  Poverty
Researchers have uncovered a link between poverty and Diabetes. In a survey in the USA, households with the lowest income-under $15,000- was found to have the highest incidence of Diabetes.

•  Having impaired glucose tolerance
Having high blood pressure or high cholesterol levels (240 mg/dl or more)
In women, having a history of gestational Diabetes or delivery of babies weighing more than 9 pounds

Complications of Diabetes
When you are not properly managing your Type 2 diabetes, you greatly increase your risk of Diabetes-related complications. Every one percent increase in your A1C level above 6 percent elevates the risk of Diabetes-related complications, including stroke, heart attack, blindness and loss of limbs. Here are some of the more common risks associated with Type 2 diabetes:

Heart Disease and Stroke

• Diabetes carries an increased risk for heart attack and stroke related to poor circulation.
• People with Diabetes are two to four times more likely to suffer strokes.
• Two-thirds of the people with Diabetes die of heart disease or stroke.

Kidney Disease

• The kidneys filter the waste products from the body.
• Diabetes can damage the kidneys, leading to failure.

Eye Complications

• Diabetes can cause eye problems and may lead to blindness.
• Every year up to 24,000 people lose their sight to Diabetes.

Nerve Damage

• Diabetes can cause nerve damage (neuropathy), which can affect feelings in arms, hands, legs or feet, and cause you to lose sensitivity to pain.
• Severe nerve damage can lead to limb amputation.

Foot Complications

• Diabetes can cause foot ulcers, nerve damage to the feet, infections and loss of blood flow resulting in possible amputation.

Skin Complications

• Diabetes can cause a range of skin disorders, such as itching, diabetic blisters, bacterial and fungus infections.
• Although these conditions are serious, you can lower your risk of Diabetes-related complications by managing your Diabetes every day.

Treatment of Diabetes

An anti-diabetic drug or oral hypoglycemic agent is used to treat diabetes mellitus. They usually work by lowering the glucose levels in the blood. There are different types of anti-diabetic drugs, and their use depends on the nature of the diabetes, age and situation of the person, as well as other factors.

Insulin is the only non-oral antidiabetic drug. It is the mainstay of treatment in type I diabetes, in which insulin production is impaired. In type-II diabetes, it is used when oral medication has become ineffective.

Antidiabetics

Sulfonylureas

Sulfonylureas were the originally popularly used oral hypoglycemic medications. They are insulin secretagogues, triggering insulin release by direct action on the KATP channel of the pancreatic beta cells. Seven types of these pills have been marketed in North America. Four of these, known as "first-generation" drugs, have been in use for some time, but not all remain available. The remaining three "second-generation" drugs are now more commonly used. They are stronger than first-generation drugs and have fewer side effects.

Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are only useful in type II diabetes, as they work by stimulating endogenous release of insulin. They work best with patients over 40 years old, who have had diabetes mellitus for under ten years. They cannot be used with type I diabetes, or diabetes of pregnancy. They can be safely used with biguanides and glitazones. The toxicity of these drugs on the whole is relatively low.

First-generation agents

• Tolbutamide (Orinase)
• Acetohexamide (Dymelor)
• Tolazamide (Tolinase)
• Chlorpropamide (Diabinese)

Second-generation agents

• Glipizide (Glucotrol)
• Glyburide (Diabeta, Micronase, Glynase)
• Glimepiride (Amaryl)

Meglitinides

Meglitinides are related to sulfonylureas. The amplification of insulin release is shorter and more intense, and they are taken with meals to boost the insulin response to each meal.

• Repaglinide (Prandin)
• Nateglinide (Starlix)

Biguanides

Biguanides reduce hepatic glucose output. Although it must be used with caution in patients with impaired liver or kidney function, metformin has become the most commonly used agent for Type 2 diabetes in children and teenagers.

• Metformin (Glucophage)
• Phenformin (DBI): used in 1960-1980s, withdrawn due to lactic acidosis risk.  

Thiazolidinediones

Thiazolidinediones, also known as "glitazones," bind to PPAR?, a type of nuclear regulatory protein involved in transcription of numerous genes regulating glucose and fat metabolism. They act as "insulin sensitizers" without increasing insulin secretion.

• Pioglitazone (Actos)
• Troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.

Alpha glucosidase inhibitors

Alpha glucosidase inhibitors are "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in Type 2 diabetes.

• Miglitol (Glyset)
• Acarbose (Precose)

Experimental agents

Many other potential drugs are currently in investigation by pharmaceutical companies. Some of these are simply newer members of one of the above classes, but some work by novel mechanisms. For example, at least one compound that enhances the sensitivity of glucokinase to rising glucose is in the stage of animal research.

Insulin by mouth

The basic appeal of oral hypoglycemic agents is that most people would prefer a pill to an injection. Unlike all the oral drugs described in this article, insulin is a protein. Protein hormones, like meat proteins, are digested in the stomach and gut.

However, the potential market for an oral form of insulin is enormous and many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the portal vein to have a measurable effect on blood sugar. One can find several research reports over the years describing promising approaches or limited success in animals, and limited human testing, but as of 2004, no products appear to be successful enough to bring to market. 

4.ACTOS EFFECTIVENESS
When is Actos best taken?

Serum concentrations of total Actos remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with Type 2 diabetes, Actos comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). 

Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for Actos and total pioglitazone at a dose of 60 mg per day.

Absorption:
Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.

Distribution:
The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Actos is extensively protein bound (> 99%) in human serum, principally to serum albumin. Actos also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (> 98%) to serum albumin. 

Metabolism:
Actos is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of Type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with Type 2 diabetes, Actos comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of Actos. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1.

Excretion and Elimination:
Following oral administration, approximately 15% to 30% of the Actos dose is recovered in the urine. Renal elimination of Actos dose is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral Actos dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Actos has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. 

5.ACTOS EFFECTS ON SPECIAL POPULATION
(How do different people react to Actos?)

Renal Insufficiency:

The serum elimination half-life of Actos, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended.

Hepatic Insufficiency :

Compared with normal controls, subjects with impaired hepatic function have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.

Actos therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal.

6.ACTOS EFFECTS ON MEDICAL CONDITIONS
(How does Actos affect your existing condition/ailment?)

Elderly:
In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.

Pediatrics:
Pharmacokinetic data in the pediatric population are not available.

Gender:
The mean Cmax and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, Actos improved glycemic control in both males and females. In controlled clinical trials, hemoglobin A1c (HbA1c) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. 

7.OTHER/ALTERNATE USES OF ACTOS
(What else does Actos treat?)

Actos is used, along with diet and exercise, in the treatment of Type 2 diabetes. 

Actos may also be used with a sulfonylurea (e.g., Diabeta, Glucotrol, Micronase, others), metformin (Glucophage), or insulin when diet and exercise plus any one of these medicines alone do not result in adequate blood sugar control.

8.ADVERSE/SIDE EFFECTS of ACTOS
(What are the side effects of Actos?)

In worldwide clinical trials, over 5900 patients with Type 2 diabetes have been treated with Actos. In U.S. clinical trials, over 4700 patients have received Actos, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer.

The overall incidence and types of adverse events reported in placebo-controlled clinical trials of Actos monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown below.

Placebo-Controlled Clinical Studies of Actos Monotherapy: Adverse Events Reported at a Frequency ³ 5% of Patients Treated with Actos
(% of Patients)
	Placebo	Actos
	N=259	N=606
Upper Respiratory Tract Infection	8.5	13.2
Headache	6.9	9.1
Sinusitis	4.6	6.3
Myalgia	2.7	5.4
Tooth Disorder	2.3	5.3
Diabetes Mellitus Aggravated	8.1	5.1
Pharyngitis	0.8	5.1

For most clinical adverse events the incidence was similar for groups treated with Actos monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with Actos and insulin compared to insulin alone.

In a 16-week, placebo-controlled Actos plus insulin trial (n=379), 10 patients treated with Actos plus insulin developed dyspnea and also, at some point during their therapy, and developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group.

The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or Actos (3.3%).

In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported.

In U.S. double-blind studies, anemia was reported in < 2% of patients treated with Actos plus sulfonylurea, metformin or insulin.

In monotherapy studies, edema was reported for 4.8% of patients treated with Actos versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with Actos and sulfonylureas compared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6.0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7.0% of patients on insulin alone. Most of these events were considered mild or moderate in intensity.

In one 16-week clinical trial of insulin plus Actos combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone, Cardiac Failure and Other Cardiac Effects).

Laboratory Abnormalities

Hematologic:
Actos may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with Actos appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with Actos. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with Actos therapy and have rarely been associated with any significant hematologic clinical effects.

Serum Transaminase Levels:
During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with Actos had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with Actos, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with Actos were withdrawn from clinical trials in the U.S. due to abnormal liver function tests.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.

CPK Levels:
During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L. Six of these patients continued to receive Actos, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical squeal. The relationship of these events to Actos therapy is unknown.