Combined Oral Contraceptive Pill mechanism of action, or “How the pill works”

Mechanism of action of oral contraceptives or "How the pill works"

This animation depicts inhibition of ovulation as the primary mechanism of the contraceptive action of sequential and combination birth control preparations. Ovulation is prevented by the suppression of the midcycle surge of FSH and LH.

Estrogens are most active in inhibiting FSH release, but at high enough doses, they also inhibit LH release. In low-dose combination products, the progestin causes LH suppression.The progestin component is also important in causing withdrawal bleeding at the end of the cycle.

FDA’s warning highlights:

• There is an increased risk of liver injury with propylthiouracil (PTU) when compared to methimazole.
• Monitor for symptoms and signs of liver injury when propylthiouracil is chosen as anti-thyroid therapy. This should be emphasized during the first six months after initiating therapy.

Read the news release

The clinical bottom line of the summary:

Premixed insulin analogues and premixed human insulin have similar effects on glycosylated hemoglobin (A1c), and rates of hypoglycemia are similar.

Premixed insulin analogues help achieve lower postprandial glucose levels than premixed human insulin.

Premixed insulin analogues help achieve lower A1c levels than long-acting insulin analogues used alone, but rates of hypoglycemia are higher.

Premixed insulin analogues are linked with more episodes of hypoglycemia than oral diabetes drugs.

Premixed insulin analogues help achieve lower A1c levels than oral diabetes drugs used alone.

Premixed Insulin Analogues: A Comparison With Other Treatments for Type 2 Diabetes. Clinician Summary Guide

The U.S. Food and Drug Administration today issued an alert to health care professionals reminding them that single-patient insulin pens and insulin cartridges should not be used to administer medication to multiple patients due to the potential risk of transmitting blood-borne pathogens such as HIV and the hepatitis viruses.

Insulin pens are pen-shaped injector devices that contain a disposable needle and either an insulin reservoir or an insulin cartridge. The devices typically contain enough insulin for a patient to self-administer several doses of insulin before the reservoir or cartridge is empty. All insulin pens are approved only for single-patient use (one device for only one patient).

 

Amy Egan, M.D., deputy director of safety at the FDA’s Division of Metabolism and Endocrinology Products in the Center for Drug Evaluation and Research declared:

“Insulin pens are not designed, and are not safe, for one pen to be used by more than one patient, even if needles are changed between patients due to the risk of transmitting blood-borne pathogens.”

Further information on the CDER website: Information for Healthcare Professionals: Risk of Transmission of Blood-borne Pathogens from Shared Use of Insulin Pens

The authors used a self-control case series analysis to study nearly 400,000 women from the UK General Practice Research Database. They included women prescribed oral alendronate or risedronate in a period of 2 years (between December 2006 and December 2008).

“We found no robust evidence of an overall long-term increased risk of atrial fibrillation or flutter associated with continued exposure to the oral bisphosphonates, alendronic acid and risedronate sodium. A possible signal for an increase in risk during the first few months of therapy with alendronic acid needs to be re-assessed in additional studies.”

Quoting the conclusions of another related paper; Relation of Bisphosphonate Therapies and Risk of Developing Atrial Fibrillation, American Journal of Cardiology:

“In conclusion, in a long-term study of >47,000 patients, we were unable to find an association between bisphosphonate therapy and AF. However, patients who received bisphosphonates were older and had more cardiovascular disease that we suspect accounts for the increased arrhythmia risk reported in other trials.”

As you can read in a previous post, FDA issued an update some months ago on the topic.

“JUPITER is notable for the unacknowledged exclusion of a population that may be at increased risk for dose-related adverse effects of rosuvastatin.”

Adriane Fugh-Berman, M.D.
Georgetown University Medical Center
Washington, DC 20007
ajf29@georgetown.edu 

“JUPITER was stopped early, after a median follow-up of 1.9 years. The number of patients who would need to be treated for 2 years to prevent the occurrence of one primary end point was 95. Ridker et al. extrapolate these results by a projection over a 5-year treatment period. This estimation should be viewed critically, since the study has most of  the characteristics of a  truncated trial”.
“The majority of randomized clinical trials that are stopped early because of an observed benefit of the treatment under investigation are industry-funded drug trials that are stopped at the first interim analysis, with  the results published  in a high-impact medical journal”.

Luc A. Pierard, M.D., Ph.D.
University Hospital Sart Tilman
B 4000 Liege, Belgium
lpierard@chu.ulg.ac.be

Read the correspondence section for further comments.

Related links:

• The JUPITER trial: Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. NEJM, November 2008.
• Expanding the Orbit of Primary Prevention — Moving beyond JUPITER
• Breaking News: The Jupiter Trial. Clinical Correlations: The NYU Internal Medicine Blog

• Agents for the treatment of thyroid disorders:
• Thyroglobulin (Proloid),Levothyroxine sodium (Synthroid, Levothroid, Levoxine), Liothyronine sodium (Cytomel)
• Antithyroid drugs: Propylthiouracil (PTU),  Methimazole (Tapazole), Iodide,  Radioactive Iodine, Propranolol (Inderal)
• Calcium & related: gluconate (Kalcinate),gluceptate,chloride, carbonate (TUMS, etc.), citrate (Citracal, etc.), glubionate (Neo-Calglucon), lactate phosphate, Dicalcium phosphate, Vitamin D₂/ergocalciferol (Deltalin, Drisdol, Calciferol), Calcitriol/1,25-(OH)₂-cholecalciferol (Rocaltrol)
• Bisphosphonates: Sodium etidronate (Didronel), Pamidronate (Aredia), Alendronate (Fosamax)
• Insulins: Regular insulin, Isophane insulin suspension (NPH insulin), Insulin Zn (Lente insulin), Extended insulin zinc suspension (Ultralente insulin).
• Oral antidiabetic drugs: Tolbutamide (Orinase), Chlorpropramide (Diabinese), Glyburide (Micronase), Glipizide (Glucotrol), Metformin (Glucophage), Acarbose (Precose), Troglitazone

Download flash cards on endocrine pharmacology

This animation is an excellent oportunity to review the drugs that act as ligands of the PPAR receptor and its subtypes (Alpha and Gamma). Novel agents that target PPAR delta are being developed.

Drugs acting on peroxisome proliferator–activated receptor-alpha (PPAR-α): fibrates

Drug members: Bezafibrate (Bezalip), Ciprofibrate (Modalim), Gemfibrozil (Lopid), Fenofibrate (TriCor)

Mechanism of action of fibrates. From Lippincott Illustrated Reviews: Pharmacology

The peroxisome proliferator–activated receptors (PPARs) are members of the nuclear receptor supergene family that regulates lipid metabolism. PPARs functions as a ligand-activated transcription factor. Upon binding to its natural ligand (fatty acids or eicosanoids) or hypolipidemic drugs, PPARs are activated. They then bind to peroxisome proliferator response elements, which are localized in numerous gene promoters. In particular, PPARs regulates the expression of genes encoding for proteins involved in lipoprotein structure and function. Fibrate-mediated gene expression ultimately leads to decreased triacylglycerol concentrations by increasing the expression of lipoprotein lipase and decreasing apo CII concentration. Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII. Fenofibrate is a prodrug, producing an active metabolite, fenofibric acid, which is responsible for the primary effects of the drug.

Peroxisome proliferator–activated receptor-gamma (PPARγ) agonists: Glitazones or thiazolidinediones (TZDs)

Members: Rosiglitazone (Avandia), Pioglitazone (Actos), Troglitazone (Rezulin)

Mechanism of action of Thiazolidinediones (TZDs) or glitazones. From Lippincott Illustrated Reviews: Pharmacology.

Although the exact mechanism by which the TZDs lower insulin resistance remains to be elucidated, they are known to target the peroxisome proliferator–activated receptor-γ (PPARγ)—a nuclear hormone receptor. Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle. Hyperglycemia, hyperinsulinemia, hypertriacylglycerolemia, and elevated HbA1c levels are improved. Interestingly, LDL levels are not affected by pioglitazone monotherapy or when the drug is used in combination with other agents, whereas LDL levels have increased with rosiglitazone. HDL levels increase with both drugs. The TZDs lead to a favorable redistribution of fat from visceral to subcutaneous tissues. [Note: Whether the adipogenic effects can be separated from those of increased insulin sensitivity is the subject of much research, particularly because of the role of obesity in this disease.] Pioglitazone and rosiglitazone can be used as monotherapy or in combination with other hypoglycemics or with insulin. The dose of insulin required for adequate glucose control in these circumstances may have to be lowered. The glitazones are recommended as a second-line alternative for patients who fail or have contraindications to metformin therapy.

On January 25, 2008, FDA announced that it would be reviewing data from the ENHANCE trial (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia). (http://www.fda.gov/cder/drug/early_comm/ezetimibe_simvastatin.htm). Preliminary results from this trial had indicated that there was no significant difference between Vytorin and simvastatin-treated patients in the thickness of the carotid (neck) arteries despite greater lowering of LDL (bad) cholesterol with Vytorin compared to simvastatin. The thickness of the carotid arteries, also known as carotid intima-media thickness or cIMT, is a marker of risk for cardiovascular disease. The preliminary results from the ENHANCE trial raised several questions, some of which involve the relationship of cIMT to LDL cholesterol levels and the role of cIMT in drug development.

The FDA has completed its review of the final clinical study report of ENHANCE. Following two years of treatment, carotid artery thickness increased by 0.011 mm in the Vytorin group and by 0.006 mm in the simvastatin group. The difference in the changes in carotid artery thickness between the two groups was not statistically significant. However, the levels of LDL cholesterol decreased by 56% in the Vytorin group and decreased by 39% in the simvastatin group. The difference in the reductions in LDL cholesterol between the two groups was statistically significant.

The results from ENHANCE do not change FDA’s position that an elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease. Based on current available data, patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about Vytorin, Zetia, or the ENHANCE trial.
ENHANCE was a randomized, double-blind, active-controlled trial conducted in patients with heterozygous familial hypercholesterolemia (HeFH). A total of 725 patients were randomized 1:1 to receive either Vytorin 10/80 (ezetimibe 10 mg plus simvastatin 80 mg) or simvastatin 80 mg for 2 years. The primary efficacy outcome was the change in ultrasound-determined carotid artery thickness (or cIMT).

Based on data from a previously-conducted cIMT study1 and the anticipated degree of cholesterol lowering with Vytorin and simvastatin, it was projected that 2 years of treatment with Vytorin in ENHANCE would lead to a decrease in cIMT of approximately 0.03 mm whereas treatment with simvastatin would lead to an increase in cIMT of approximately 0.02 mm. There are several possible explanations for why the larger reduction in LDL cholesterol observed in the Vytorin group did not translate into significant improvement in cIMT. These include:

• enrollment of a patient population who had received prior lipid-altering or statin therapy and had relatively normal cIMT values at baseline which may make it harder to demonstrate a reduction or improvement in cIMT with Vytorin compared with simvastatin therapy

• the 2-year duration of ENHANCE which may have been too short to see a favorable effect of cholesterol lowering on cIMT

• some other unknown properties of ezetimibe that may negate the beneficial effects of LDL lowering on cIMT.

An ongoing trial known as IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) is examining whether treatment with Vytorin reduces the risk for cardiovascular events (composite endpoint of CV death, major coronary events, and stroke) compared with simvastatin alone. This trial of 18,000 patients is scheduled to be completed in 2012. IMPROVE-IT will provide additional data regarding Vytorin’s effect on the risk for cardiovascular disease.

Pending the results from IMPROVE-IT, patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about these medications.

Ezetimibe (Zetia) is an inhibitor of intestinal cholesterol absorption approved to reduce LDL cholesterol levels. Simvastatin (Zocor) is a lipid-lowering drug (“statin”) approved to reduce LDL (bad) cholesterol and increase HDL (good) cholesterol levels and reduce the risk of cardiovascular events such as heart attack and stroke. Vytorin is a combination of ezetimibe and simvastatin approved for reducing LDL and increasing HDL cholesterol levels.

This follow-up communication is in keeping with FDA’s commitment to informing the public about its ongoing safety reviews of drugs.

The FDA urges both healthcare professionals and patients to report side effects from the use of lipid lowering drugs to the FDA’s MedWatch Adverse Event Reporting program
on-line at www.fda.gov/medwatch/report.htm
by returning the postage-paid FDA form 3500 (available in PDF format at www.fda.gov/medwatch/getforms.htm) to 5600 Fishers Lane, Rockville, MD 20852-9787
faxing the form to 1-800-FDA-0178
by phone at 1-800-332-1088

1 Smilde T, et al. Effect of aggressive versus conventional lipid lowering on athersclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomized double-blind study; Lancet 2001;357:577-581.

Source: FDA CER. Update of Safety Review Follow-up to the January 25, 2008 Early Communication about an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor)

Ibandronic acid

Bondronat (Hospira)
vials containing 6 mg/6 mL
Approved indications: hypercalcaemia, bony metastases of breast cancer
Australian Medicines Handbook section 10.3.1

Bisphosphonates can reduce the hypercalcaemia of malignant disease by inhibiting the resorption of bone. Clodronate, pamidronate and zoledronic acid are already available for this indication. They are now joined by ibandronic acid which has been approved for patients, with or without metastases, who have tumour-induced hypercalcaemia. It is also approved for the treatment of metastatic bone disease in patients with breast cancer.

When ibandronic acid is given intravenously, it should be diluted and infused over two hours. For hypercalcaemia the dose is determined by the serum calcium, after correction for the albumin concentration. Patients with metastatic breast cancer can be given an intravenous infusion every four weeks or a daily oral dose. Ibandronic acid should not be taken with food as this reduces its bioavailability by 90%. The tablets must be swallowed whole with water and the patient must not lie down for 30 minutes afterwards.

About half of the dose is absorbed by bone. The remainder is excreted unchanged in the urine. No dose adjustment is suggested for hepatic impairment, but the dose should be reduced in patients with severe renal impairment.

A randomised phase II trial studied 174 cancer patients with hypercalcaemia.[1] These patients were given ibandronic acid in one of three different doses. The best response to treatment was seen in the patients given the highest dose (2 mg). In this group of 55 patients, 37 became normocalcaemic. Patients with higher baseline concentrations of calcium also responded better to the highest dose.

The efficacy of intravenous ibandronic acid, given every 3—4 weeks, was assessed in a placebo-controlled trial of 466 women with breast cancer and bony metastases. Their median time in the study was 13 months with placebo and 18 months with ibandronic acid. Although a 2 mg dose was not statistically different from placebo, the rate of skeletal complications was reduced in women given ibandronic acid 6 mg. At that dose there were 2.65 ‘bone events’ per patient compared with 3.64 in the placebo group. (These events included fractures and other bony complications requiring treatment.) The women taking ibandronic acid 6 mg also had less bone pain.[2]

Oral ibandronic acid was assessed in 435 women with bony metastases randomised to take 20 mg, 50 mg or a placebo daily for up to 96 weeks. The mean number of bone events per patient was 1.36 with 20 mg, 1.43 with 50 mg and 2.23 with placebo. Although the two doses of ibandronic acid had similar efficacy the higher dose is recommended for clinical use.[3]

The adverse effects of oral treatment include dyspepsia, oesophagitis, abdominal pain, nausea and hypocalcaemia. Intravenous ibandronic acid is associated with fever or a flu-like illness, asthenia, diarrhoea, vomiting, headache and myalgia. Calcium and renal function should be monitored during treatment. The patient must have an adequate intake of calcium and vitamin D if there is a risk of hypocalcaemia. They should also have a dental check-up before treatment because of the association between bisphosphonates and osteonecrosis of the jaw.

A Cochrane review has concluded that bisphosphonates are effective treatment for the bony metastases of breast cancer, although they have no effect on survival. It did not report if ibandronic acid had a clinical advantage over other bisphosphonates.4 An analysis in the UK found that oral ibandronic acid is more cost-effective than intravenous pamidronate or zoledronic acid, but this could reflect the cost of infusions rather than greater efficacy.5 Comparative trials are needed.

manufacturer provided all requested information (provided by Roche)

References*†
[1] Pecherstorfer M, Herrmann Z, Body JJ, Manegold C, Degardin M, Clemens MR, et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996;14:268-76.
[2] Body JJ, Diel IJ, Lichinitser MR, Kreuser ED, Dornoff W, Gorbunova VA, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399-405.
[3] Tripathy D, Lichinitzer M, Lazarev A, MacLachlan SA, Apffelstaedt J, Budde M, et al. Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial. Ann Oncol 2004;15:743-50.
[4] Pavlakis N, Schmidt RL, Stockler M. Bisphosphonates for breast cancer. The Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD003474. DOI: 10.1002/14651858.CD003474.pub2.
[5] De Cock E, Hutton J, Canney P, Body JJ, Barrett-Lee P, Neary MP, et al. Cost-effectiveness of oral ibandronate versus IV zoledronic acid or IV pamidronate for bone metastases in patients receiving oral hormonal therapy for breast cancer in the United Kingdom. Clin Ther 2005;27:1295-310.

Source: Australian Prescriber. New drugs: ibandronic acid. Volume 31 Number 3 – June 2008.