Focus On , Pharmacology

Pimobendan and Heart Disease

Ashley B. Saunders DVM, DACVIM (Cardiology)

Ashley B. Saunders, DACVIM (Cardiology), is a professor of cardiology in the Department of Small Animal Clinical Sciences at Texas A&M University College of Veterinary Medicine and Biomedical Sciences. Her interests include interventional cardiology and advanced imaging, heart failure management, and educational technology. She is the recipient of multiple teaching awards and is a Montague Center for Teaching Excellence Scholar.

Sonya G. Gordon DVM, DVSc, DACVIM (Cardiology)

Sonya G. Gordon, DVM, DVSc, DACVIM (Cardiology), is an associate professor of cardiology in the Department of Small Animal Clinical Sciences at Texas A&M University College of Veterinary Medicine and Biomedical Sciences where she is part of a busy progressive cardiology program. She is routinely an invited speaker at local, national and international veterinary meetings. Although she considers herself a clinician and teacher first her research interests include canine chronic valve disease, dilated cardiomyopathy, imaging, interventional procedures and clinical trials. She has published numerous manuscripts and book chapters and co-authored a practical small animal clinical cardiology book entitled The ABCDs of Small Animal Cardiology.

Pimobendan and Heart Disease
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Pimobendan is a benzimidazole-pyridazinone derivative, labeled for use in dogs to manage congestive heart failure (CHF) resulting from dilated cardiomyopathy (DCM) or degenerative mitral valve disease (DMVD) in the United States. On the basis of its positive inotropic effects combined with arteriovenous dilation, it is classified as an inodilator.1

In this article, we provide relevant information about the pharmacology of pimobendan based on a review of the literature providing evidence to support its use for a variety of indications. As additional research is published, the indications and recommended uses for pimobendan continue to evolve.

Formulation and Dosing

Pimobendan is available as Vetmedin (vetmedin.com) in oblong, half-scored chewable tablets (1.25 mg, 2.5 mg, 5 mg, or 10 mg). Because the stability and efficacy of the drug in suspension are unknown, reformulating as an oral suspension should be avoided. In some countries outside of the United States, an intravenous preparation is available.

For dogs, the labeled dosage recommendation for pimobendan is 0.25 to 0.3 mg/kg PO q12h. The total daily dose can be administered in 2 unequal portions by using whole or half tablets.
For initial use, especially if a more rapid onset of action is desired, the tablets should be administered on an empty stomach; however, for more chronic use, they can be administered with food. In dogs and cats, the oral preparation is rapidly absorbed; peak effect occurs within 2 to 4 hours in dogs and 0.9 hours in cats.1,2

Mechanisms of Action

Increased Cardiac Contractility

The positive inotropic effects of pimobendan are mediated through a combination of 1) increased cyclic adenosine monophosphate mediated by phosphodiesterase III (PDEIII) inhibition, and 2) sensitization of the cardiac contractile apparatus to intracellular calcium. Calcium sensitization results in a positive inotropic effect without increasing myocardial oxygen demand.

Vasodilation

Balanced vasodilatory effects are mediated predominately through PDEIII inhibition in arterial and venous vascular smooth muscle. Additional endothelial-mediated vasodilation mechanisms may also contribute to this action and may be linked to the medication’s beneficial effect in the treatment of pulmonary hypertension.3

Anticoagulation and Other Properties

In platelets, PDEIII inhibition mediates antithrombotic properties, leading to reduced platelet aggregation. This effect has been investigated in other pyridazinone-based compounds as well as pimobendan.4 In a study of healthy dogs, pimobendan mildly inhibited platelet aggregation but at a concentration well above a clinically relevant dose.5 In mice in heart failure, pimobendan reduced some of the adverse cytokine concentrations.6

Indications

Pimobendan is used to treat preclinical and clinical DCM and DMVD (TABLE 1, Box 1).


BOX 1.

Indications

The American College of Veterinary Internal Medicine (ACVIM) consensus statement describes 4 stages of heart disease and failure. The ACVIM consensus statement for DMVD outlines a staging system for preclinical (stage B) and clinical (stages C and D) disease.7

Preclinical DCM (Stage B2)

This stage is characterized by systolic dysfunction (dilated left ventricle in systole) that is usually associated with left ventricular dilation in diastole, with or without left atrial enlargement, and with or without supraventricular and ventricular arrhythmias. Abnormalities are identified by screening with echocardiography and electrocardiography (ECG). The primary diagnostic criterion for preclinical DCM is significant systolic left ventricular dysfunction. Therefore, echocardiography is required to establish a diagnosis (see CASE 1).

Research data from studies of Doberman pinschers8 and Irish wolfhounds9 with preclinical DCM show that pimobendan use was associated with

  • Reduced left ventricular size in systole and diastole8
  • Delayed average time to onset of CHF or sudden death8,9
  • Longer overall survival times8,9

Pimobendan may be considered for use in other breeds with echocardiographic confirmation of preclinical DCM (TABLE 1).

Clinical DCM (Stages C and D)

Clinical DCM is characterized by left ventricular systolic dysfunction and dilation complicated by CHF. It is manifested by pulmonary edema, with or without ascites, and, more rarely, pleural effusion, with or without significant ventricular arrhythmias or atrial fibrillation.

Pimobendan added to heart failure therapy (furosemide and benazepril) improves clinical status, delays onset of refractory signs of heart failure, and increases survival times.10,11

Preclinical DMVD (Stage B2)

DMVD is most common in middle-aged to older small breed dogs and is characterized by a left-sided systolic murmur over the mitral valve (left apex). Dogs with stage B2 heart disease show radiographic and echocardiographic evidence of heart enlargement without clinical signs attributable to heart disease. Stage B2 will progress to CHF in only 30% of dogs; however, all of these dogs are at risk for disease progression characterized by progressive heart enlargement.12

Pimobendan delays the onset of CHF, in part through reduction in heart size, and increases survival times.13,14 Pimobendan use is recommended for dogs that have a confirmed diagnosis of preclinical DMVD and radiographic and echocardiographic heart size measurements that meet or exceed the following criteria used in the EPIC study13 (see CASE 2):

  • Radiographic vertebral heart size (VHS) >10.5
  • Two-dimensional echocardiographic left atrium/aorta ratio (LA/Ao-2D) ≥1.6
  • Echocardiographic normalized left ventricular internal dimension in diastole indexed to body weight (LVIDdN) ≥1.715

If echocardiography is not available but the signalment and murmur characteristics support DMVD and the dog has radiographic evidence of cardiomegaly with a VHS ≥11.5, pimobendan can be considered on the basis of recommendations created by the Cardiac Education Group (TABLE 1).16 If the VHS is >10.5 but <11.5, echocardiography is strongly recommended to guide recommendations regarding pimobendan use.16

Clinical DMVD (Stages C and D)

Characteristics of these stages are similar to those of stage B2 but include past or present clinical signs consistent with CHF. For dogs with clinical DMVD, pimobendan doubles the time to sudden death, treatment failure, or euthanasia for cardiac reasons.17 In dogs with at least moderate pulmonary hypertension, it decreases tricuspid regurgitation outflow velocities, indicating reduced pulmonary pressures.

Treatment with pimobendan is clearly indicated for dogs with stage B2 (asymptomatic that meet EPIC heart size entry criteria) or stages C and D (symptomatic) DMVD with or without pulmonary hypertension, characterized by elevated left atrial pressures. In dogs with concurrent pulmonary hypertension secondary to DMVD, the positive effects are probably multifactorial. The effects may be secondary to reduced left atrial pressure, increased right heart systolic function associated with increased inotropy, and reduced pulmonary vascular resistance associated with vasodilation.18


Left-Sided and Right-Sided CHF

CHF can develop for reasons other than DMVD or DCM. To justify initiation of pimobendan when the underlying CHF etiology is unclear or for symptomatic patients when standard therapy has failed (stage D) (TABLE 1), echocardiography is typically indicated. When in doubt, consultation with a cardiologist is recommended.

Other Indications

  • Congenital heart disease with volume overload (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect, mitral or tricuspid valve dysplasia) complicated by CHF.
  • Congenital heart disease characterized by obstruction (e.g., subaortic stenosis, pulmonic stenosis) with secondary myocardial failure in a patient with symptoms refractory to standard therapy. For these cases, we strongly recommend consultation with a cardiologist before initiation of pimobendan.
  • Pulmonary hypertension unrelated to DMVD, resulting in right-sided CHF (ascites) refractory to standard therapy (i.e., cor pulmonale, advanced heartworm disease, pulmonary thromboembolism). For these patients, pimobendan can be added to other therapies; however, we recommend first consulting a cardiologist.

Pimobendan seems to be safe and well tolerated. Reported adverse effects are relatively rare and are typically limited to gastrointestinal upset associated with the chewable tablets.

CONTRAINDICATION

When ascites is the result of pericardial effusion that requires pericardiocentesis, use of pimobendan is not recommended.

PRECAUTIONS

Pimobendan seems to be safe and well tolerated. Reported adverse effects are relatively rare and are typically limited to gastrointestinal upset associated with the chewable tablets. Significant overdose has reportedly resulted in pimobendan toxicity, manifested as severe tachycardia and mild changes in blood pressure.19

Pimobendan should be used cautiously in patients
with an outflow tract obstruction, which includes
the following:

  • Subaortic stenosis
  • Pulmonic stenosis
  • Systolic anterior motion of the mitral valve
  • Asymmetric septal hypertrophy

If pimobendan is given to a patient with outflow tract obstruction or low systemic blood pressure, to ensure that it is well tolerated, you should reassess both blood pressure and heart rate approximately 1 to 2 hours after the first dose of pimobendan is given.

Interactions with other drugs have not been reported.

TAKE-HOME POINTS

  • Pimobendan is an inodilator labeled for use in dogs with CHF resulting from DCM or DMVD.
  • Pimobendan is recommended for the treatment of DMVD stages B2 (that meet EPIC criteria), C, and D and DCM stages B2, C, and D.
  • Pimobendan can be beneficial used alone or in combination with other cardiac drugs.
    Beneficial effects for dogs in stage B2 DMVD or DCM include prolongation of symptom-free and overall survival times.
  • Beneficial effects for dogs in stages C/D DMVD or DCM include reduced clinical signs and heart size and increased survival times.
  • Pimobendan should not be used in dogs with ascites resulting from pericardial effusion.

CASE SCENARIOS

Case 1

FIGURE 1. Dog with DCM. (A) Lead II ECG documenting sinus arrhythmia with a single ventricular premature contraction (25 mm/s; 10 mm/mV); (B) echocardiogram of the left atrium with the LA/Ao-2D; (C) echocardiogram of the short axis left ventricle M-mode with the left ventricular internal dimension in diastole (LVIDd) and in systole (LVIDs).

You are performing an annual wellness examination of a 7-year-old, 31-kg, spayed female Doberman pinscher. You auscultate a grade 2/6 systolic, left apical heart murmur and an arrhythmia. No clinical signs have been reported. The signalment and auscultation characteristics support a possible diagnosis of DCM. ECG (3 minute) and echocardiography are performed (FIGURE 1).

Does this dog have preclinical DCM? Yes, this dog has preclinical DCM (stage B2) on the basis of echocardiographic evidence of left ventricular dilation in systole of 4 cm (reference range 2.9 ± 0.3 cm) and diastole of 4.8 cm (reference range 3.8 ± 0.2 cm), low fractional shortening (16.6%; reference is >24%), left atrial dilation, and normal mitral valve morphology.20 Mild mitral regurgitation was documented as a consequence of the left ventricular dilation. The ECG demonstrated a sinus arrhythmia with 1 ventricular premature contraction.

What should you do next? Consider further diagnostics, including thyroid assessment and a 24-hour ambulatory ECG (Holter examination). Hypothyroidism could be a contributing cause for the systolic dysfunction. Holter examination findings could better characterize the frequency and severity of the ventricular arrhythmias and help you determine if there is any need for antiarrhythmic therapy at this time.

No antiarrhythmic medication is indicated at this time because the dog is asymptomatic and showed only 1 ventricular premature contraction on a 3-minute ECG. Holter monitoring, whether performed now or in the future, may lead you to alter this decision.

Is pimobendan recommended for this dog? Yes, initiation of pimobendan is recommended on the basis of the PROTECT study results.8 In addition, initiation of an angiotensin-converting enzyme (ACE) inhibitor can be considered according to findings of a retrospective study of Doberman pinschers, which suggests that these drugs delay disease progression.21 However, before starting an ACE inhibitor, you should assess serum biochemistry.

Pimobendan added to heart failure therapy (furosemide and benazepril) improves clinical status, delays onset of refractory signs of heart failure, and increases survival times.10,11

Case 2

FIGURE 2. Dog with DMVD. (A) Right lateral thoracic radiograph demonstrating measurements for VHS; (B) echocardiogram of the left atrium with the LA/Ao-2D; (C) echocardiogram of the short axis left ventricle M-mode with the LVIDd and LVIDs.

You are performing an annual wellness examination of a 9-year-old, 12-kg, spayed female Jack Russell terrier. You auscultate a grade 4/6 systolic, left apical heart murmur. No clinical signs are reported, and the signalment and murmur characteristics support a probable diagnosis of preclinical (stage B1 or B2) DMVD.

Thoracic radiography and echocardiography are performed to determine if the dog has cardiomegaly severe enough to meet or exceed the EPIC criteria for initiating pimobendan (FIGURE 2).13

Is this dog a candidate for pimobendan therapy? Yes, initiating pimobendan therapy is recommended. This dog meets the EPIC criteria (VHS >10.5, LA/Ao-2D ≥1.6, LVIDdN ≥1.7). The echocardiogram confirms DMVD: thick mitral valve leaflets and an eccentric jet of mitral regurgitation. The VHS is 10.9, and the LA/Ao-2D measured as depicted on FIGURE 2 is 2.1. The LVIDd is increased to 4.2 cm (reference range 2.8 to 4.0 cm),20 and the LVIDdN is 2.0 (FIGURE 2).

Learn More

In the absence of an equally effective drug licensed for use in cats, pimobendan has been used in patients of this species. To download information about off-label use of pimobendan in cats, click here.

References

  1. Boehringer Ingelheim Vetmedica, Inc. Vetmedin (pimobendan) chewable tablets. vetmedin.com/documents/vetmedin_pi.pdf. Accessed January 2017.
  2. Hanzlicek AS, Gehring R, Kukanich B, et al. Pharmacokinetics of oral pimobendan in healthy cats. J Vet Cardiol 2012;14(4):489-496.
  3. Yoshiyuki R, Nakata TM, Fukayama T, et al. Pimobendan improves right ventricular myocardial contraction and attenuates pulmonary arterial hypertension in rats with monocrotaline-induced pulmonary arterial hypertension. J Med Ultrason 2014;41(2):173-180.
  4. Sotelo E, Fraiz N, Yanez M, et al. Pyridazines. Part 28: 5-alkylidene-6-phenyl-3(2H)-pyridazinones, a new family of platelet aggregation inhibitors. Bioorg Med Chem Lett 2002;12(12):1575-1577.
  5. Shipley EA, Hogan DF, Fiakui NN, et al. In vitro effect of pimobendan on platelet aggregation in dogs. Am J Vet Res 2013;74(3):403-407.
  6. Matsumori A, Sasayama S. The role of inflammatory mediators in the failing heart: immunomodulation of cytokines in experimental models of heart failure. Heart Fail Rev 2001;6(2):129-136.
  7. Atkins C, Bonagura J, Ettinger S, et al. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med 2009;23(6):1142-1150.
  8. Summerfield NJ, Boswood A, O’Grady MR, et al. Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman pinschers with preclinical dilated cardiomyopathy (The PROTECT Study). J Vet Intern Med 2012;26(6):1337-1349.
  9. Vollmar AC, Fox PR. Long-term outcome of Irish wolfhound dogs with preclinical cardiomyopathy, atrial fibrillation, or both treated with pimobendan, benazepril hydrochloride, or methyldigoxin monotherapy. J Vet Intern Med 2016;30(2):553-559.
  10. Fuentes VL, Corcoran B, French A, et al. A double-blind, randomized, placebo-controlled study of pimobendan in dogs with dilated cardiomyopathy. J Vet Intern Med 2002;16(3):255-261.
  11. O’Grady MR, Minors SL, O’Sullivan ML, Home R. Effect of pimobendan on case fatality rate in Doberman pinschers with congestive heart failure caused by dilated cardiomyopathy. J Vet Intern Med 2008;22(4):897-904.
  12. Borgarelli M, Savarino P, Crosara S, et al. Survival characteristics and prognostic variables of dogs with mitral regurgitation attributable to myxomatous valve disease. J Vet Intern Med 2008;22(1):120-128.
  13. Boswood A, Haggstrom J, Gordon SG, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: the EPIC study−a randomized clinical trial. J Vet Intern Med 2016;30(6):1765-1779.
  14. Boswood A, Gordon SG, Haggstrom J, et al. Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with preclinical valve disease receiving pimobendan or placebo: the EPIC Study. J Vet Intern Med 2017; 32(1):72-85.
  15. Cornell CC, Kittleson MD, Della Torre P, et al. Allometric scaling of M-mode cardiac measurements in normal adult dogs. J Vet Intern Med 2004;18(3):311–321.
  16. Church WM, Bonagura JD, Gordon SG, et al. The EPIC trial: pimobendan in preclinical myxomatous mitral valve disease. cardiaceducationgroup.org/wp-content/uploads/2016/12/CEG_Recommendations_EPIC_121316.pdf. Accessed March 2017.
  17. Haggstrom J, Boswood A, O’Grady M, et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST Study. J Vet Intern Med 2008;22(5):1124-1135.
  18. Kellihan HB, Stepien RL. Pulmonary hypertension in canine degenerative mitral valve disease. J Vet Cardiol 2012;14(1):149-164.
  19. Reinker LN, Lee JA, Hovda LR, Rishniw M. Clinical signs of cardiovascular effects secondary to suspected pimobendan toxicosis in five dogs. J Am Anim Hosp Assoc 2012;48(4):250-255.
  20. Boon JA. Veterinary Echocardiography. 2nd ed. West Sussex: Wiley-Blackwell; 2011:531-537.
  21. O’Grady MR, O’Sullivan ML, Minors SL, Home R. Efficacy of benazepril hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman pinschers. J Vet Intern Med 2009;23(5):977–983.

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Code</label> </span><span class='ginput_right address_country' id='input_6_10_6_container' > <select name='input_10.6' id='input_6_10_6' aria-required="true"><option value='' selected='selected'></option><option value='Afghanistan' >Afghanistan</option><option value='Åland Islands' >Åland Islands</option><option value='Albania' >Albania</option><option value='Algeria' >Algeria</option><option value='American Samoa' >American Samoa</option><option value='Andorra' >Andorra</option><option value='Angola' >Angola</option><option value='Anguilla' >Anguilla</option><option value='Antarctica' >Antarctica</option><option value='Antigua and Barbuda' >Antigua and Barbuda</option><option value='Argentina' >Argentina</option><option value='Armenia' >Armenia</option><option value='Aruba' >Aruba</option><option value='Australia' >Australia</option><option value='Austria' >Austria</option><option value='Azerbaijan' >Azerbaijan</option><option value='Bahamas' >Bahamas</option><option value='Bahrain' >Bahrain</option><option value='Bangladesh' >Bangladesh</option><option value='Barbados' >Barbados</option><option value='Belarus' >Belarus</option><option value='Belgium' >Belgium</option><option value='Belize' >Belize</option><option value='Benin' >Benin</option><option value='Bermuda' >Bermuda</option><option value='Bhutan' >Bhutan</option><option value='Bolivia' >Bolivia</option><option value='Bonaire, Sint Eustatius and Saba' >Bonaire, Sint Eustatius and Saba</option><option value='Bosnia and Herzegovina' >Bosnia and Herzegovina</option><option value='Botswana' >Botswana</option><option value='Bouvet Island' >Bouvet Island</option><option value='Brazil' >Brazil</option><option value='British Indian Ocean Territory' >British Indian Ocean Territory</option><option value='Brunei Darussalam' >Brunei Darussalam</option><option value='Bulgaria' >Bulgaria</option><option value='Burkina Faso' >Burkina Faso</option><option value='Burundi' >Burundi</option><option value='Cambodia' >Cambodia</option><option value='Cameroon' >Cameroon</option><option value='Canada' >Canada</option><option value='Cape Verde' >Cape Verde</option><option value='Cayman Islands' >Cayman Islands</option><option value='Central African Republic' >Central African Republic</option><option value='Chad' >Chad</option><option value='Chile' >Chile</option><option value='China' >China</option><option value='Christmas Island' >Christmas Island</option><option value='Cocos Islands' >Cocos Islands</option><option value='Colombia' >Colombia</option><option value='Comoros' >Comoros</option><option value='Congo, Democratic Republic of the' >Congo, Democratic Republic of the</option><option value='Congo, Republic of the' >Congo, Republic of the</option><option value='Cook Islands' >Cook Islands</option><option value='Costa Rica' >Costa Rica</option><option value='Côte d&#039;Ivoire' >Côte d&#039;Ivoire</option><option value='Croatia' >Croatia</option><option value='Cuba' >Cuba</option><option value='Curaçao' >Curaçao</option><option value='Cyprus' >Cyprus</option><option value='Czech Republic' >Czech Republic</option><option value='Denmark' >Denmark</option><option value='Djibouti' >Djibouti</option><option value='Dominica' >Dominica</option><option value='Dominican Republic' >Dominican Republic</option><option value='Ecuador' >Ecuador</option><option value='Egypt' >Egypt</option><option value='El Salvador' >El Salvador</option><option value='Equatorial Guinea' >Equatorial Guinea</option><option value='Eritrea' >Eritrea</option><option value='Estonia' >Estonia</option><option value='Eswatini (Swaziland)' >Eswatini (Swaziland)</option><option value='Ethiopia' >Ethiopia</option><option value='Falkland Islands' >Falkland Islands</option><option value='Faroe Islands' >Faroe Islands</option><option value='Fiji' >Fiji</option><option value='Finland' >Finland</option><option value='France' >France</option><option value='French Guiana' >French Guiana</option><option value='French Polynesia' >French Polynesia</option><option value='French Southern Territories' >French Southern Territories</option><option value='Gabon' >Gabon</option><option value='Gambia' >Gambia</option><option value='Georgia' >Georgia</option><option value='Germany' >Germany</option><option value='Ghana' >Ghana</option><option value='Gibraltar' >Gibraltar</option><option value='Greece' >Greece</option><option value='Greenland' >Greenland</option><option value='Grenada' >Grenada</option><option value='Guadeloupe' >Guadeloupe</option><option value='Guam' >Guam</option><option value='Guatemala' >Guatemala</option><option value='Guernsey' >Guernsey</option><option value='Guinea' >Guinea</option><option value='Guinea-Bissau' >Guinea-Bissau</option><option value='Guyana' >Guyana</option><option value='Haiti' >Haiti</option><option value='Heard and McDonald Islands' >Heard and McDonald Islands</option><option value='Holy See' >Holy See</option><option value='Honduras' >Honduras</option><option value='Hong Kong' >Hong Kong</option><option value='Hungary' >Hungary</option><option value='Iceland' >Iceland</option><option value='India' >India</option><option value='Indonesia' >Indonesia</option><option value='Iran' >Iran</option><option value='Iraq' >Iraq</option><option value='Ireland' >Ireland</option><option value='Isle of Man' >Isle of Man</option><option value='Israel' >Israel</option><option value='Italy' >Italy</option><option value='Jamaica' >Jamaica</option><option value='Japan' >Japan</option><option value='Jersey' >Jersey</option><option value='Jordan' >Jordan</option><option value='Kazakhstan' >Kazakhstan</option><option value='Kenya' >Kenya</option><option value='Kiribati' >Kiribati</option><option value='Kuwait' >Kuwait</option><option value='Kyrgyzstan' >Kyrgyzstan</option><option value='Lao People&#039;s Democratic Republic' >Lao People&#039;s Democratic Republic</option><option value='Latvia' >Latvia</option><option value='Lebanon' >Lebanon</option><option value='Lesotho' >Lesotho</option><option value='Liberia' >Liberia</option><option value='Libya' >Libya</option><option value='Liechtenstein' >Liechtenstein</option><option value='Lithuania' >Lithuania</option><option value='Luxembourg' >Luxembourg</option><option value='Macau' >Macau</option><option value='Macedonia' >Macedonia</option><option value='Madagascar' >Madagascar</option><option value='Malawi' >Malawi</option><option value='Malaysia' >Malaysia</option><option value='Maldives' >Maldives</option><option value='Mali' >Mali</option><option value='Malta' >Malta</option><option value='Marshall Islands' >Marshall Islands</option><option value='Martinique' >Martinique</option><option value='Mauritania' >Mauritania</option><option value='Mauritius' >Mauritius</option><option value='Mayotte' >Mayotte</option><option value='Mexico' >Mexico</option><option value='Micronesia' >Micronesia</option><option value='Moldova' >Moldova</option><option value='Monaco' >Monaco</option><option value='Mongolia' >Mongolia</option><option value='Montenegro' >Montenegro</option><option value='Montserrat' >Montserrat</option><option value='Morocco' >Morocco</option><option value='Mozambique' >Mozambique</option><option value='Myanmar' >Myanmar</option><option value='Namibia' >Namibia</option><option value='Nauru' >Nauru</option><option value='Nepal' >Nepal</option><option value='Netherlands' >Netherlands</option><option value='New Caledonia' >New Caledonia</option><option value='New Zealand' >New Zealand</option><option value='Nicaragua' >Nicaragua</option><option value='Niger' >Niger</option><option value='Nigeria' >Nigeria</option><option value='Niue' >Niue</option><option value='Norfolk Island' >Norfolk Island</option><option value='North Korea' >North Korea</option><option value='Northern Mariana Islands' >Northern Mariana Islands</option><option value='Norway' >Norway</option><option value='Oman' >Oman</option><option value='Pakistan' >Pakistan</option><option value='Palau' >Palau</option><option value='Palestine, State of' >Palestine, State of</option><option value='Panama' >Panama</option><option value='Papua New Guinea' >Papua New Guinea</option><option value='Paraguay' >Paraguay</option><option value='Peru' >Peru</option><option value='Philippines' >Philippines</option><option value='Pitcairn' >Pitcairn</option><option value='Poland' >Poland</option><option value='Portugal' >Portugal</option><option value='Puerto Rico' >Puerto Rico</option><option value='Qatar' >Qatar</option><option value='Réunion' >Réunion</option><option value='Romania' >Romania</option><option value='Russia' >Russia</option><option value='Rwanda' >Rwanda</option><option value='Saint Barthélemy' >Saint Barthélemy</option><option value='Saint Helena' >Saint Helena</option><option value='Saint Kitts and Nevis' >Saint Kitts and Nevis</option><option value='Saint Lucia' >Saint Lucia</option><option value='Saint Martin' >Saint Martin</option><option value='Saint Pierre and Miquelon' >Saint Pierre and Miquelon</option><option value='Saint Vincent and the Grenadines' >Saint Vincent and the Grenadines</option><option value='Samoa' >Samoa</option><option value='San Marino' >San Marino</option><option value='Sao Tome and Principe' >Sao Tome and Principe</option><option value='Saudi Arabia' >Saudi Arabia</option><option value='Senegal' >Senegal</option><option value='Serbia' >Serbia</option><option value='Seychelles' >Seychelles</option><option value='Sierra Leone' >Sierra Leone</option><option value='Singapore' >Singapore</option><option value='Sint Maarten' >Sint Maarten</option><option value='Slovakia' >Slovakia</option><option value='Slovenia' >Slovenia</option><option value='Solomon Islands' >Solomon Islands</option><option value='Somalia' >Somalia</option><option value='South Africa' >South Africa</option><option value='South Georgia' >South Georgia</option><option value='South Korea' >South Korea</option><option value='South Sudan' >South Sudan</option><option value='Spain' >Spain</option><option value='Sri Lanka' >Sri Lanka</option><option value='Sudan' >Sudan</option><option value='Suriname' >Suriname</option><option value='Svalbard and Jan Mayen Islands' >Svalbard and Jan Mayen Islands</option><option value='Sweden' >Sweden</option><option value='Switzerland' >Switzerland</option><option value='Syria' >Syria</option><option value='Taiwan' >Taiwan</option><option value='Tajikistan' >Tajikistan</option><option value='Tanzania' >Tanzania</option><option value='Thailand' >Thailand</option><option value='Timor-Leste' >Timor-Leste</option><option value='Togo' >Togo</option><option value='Tokelau' >Tokelau</option><option value='Tonga' >Tonga</option><option value='Trinidad and Tobago' >Trinidad and Tobago</option><option value='Tunisia' >Tunisia</option><option value='Turkey' >Turkey</option><option value='Turkmenistan' >Turkmenistan</option><option value='Turks and Caicos Islands' >Turks and Caicos Islands</option><option value='Tuvalu' >Tuvalu</option><option value='Uganda' >Uganda</option><option value='Ukraine' >Ukraine</option><option value='United Arab Emirates' >United Arab Emirates</option><option value='United Kingdom' >United Kingdom</option><option value='United States' >United States</option><option value='Uruguay' >Uruguay</option><option value='US Minor Outlying Islands' >US Minor Outlying Islands</option><option value='Uzbekistan' >Uzbekistan</option><option value='Vanuatu' >Vanuatu</option><option value='Venezuela' >Venezuela</option><option value='Vietnam' >Vietnam</option><option value='Virgin Islands, British' >Virgin Islands, British</option><option value='Virgin Islands, U.S.' >Virgin Islands, U.S.</option><option value='Wallis and Futuna' >Wallis and Futuna</option><option value='Western Sahara' >Western Sahara</option><option value='Yemen' >Yemen</option><option value='Zambia' >Zambia</option><option value='Zimbabwe' >Zimbabwe</option></select> <label for='input_6_10_6' id='input_6_10_6_label' 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