SEMINTRA- telmisartan solution

Drug Details [pdf]

SPL UNCLASSIFIED SECTION

For oral use in cats only
Angiotensin II Receptor Blocker
CAUTION

Federal law restricts this drug to use by or on the order of a licensed veterinarian.
DESCRIPTION

SEMINTRA (telmisartan oral solution) is a clear, colorless to yellowish viscous solution containing 10 mg/mL telmisartan. Telmisartan is an orally active, non-peptide, selective angiotensin II subtype 1 (AT1) receptor blocker. The chemical name of telmisartan is 4'-[(1,4’-dimethyl-2'propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is C33H30N4O2, its molecular weight is 514.63, and its structural formula is:
INDICATION

SEMINTRA is indicated for the control of systemic hypertension in cats.
DOSAGE AND ADMINISTRATION

Always provide the Client Information Sheet with each prescription.

The initial dose of SEMINTRA is 1.5 mg/kg (0.68 mg/lb) orally twice daily for 14 days, followed by 2 mg/kg (0.91 mg/lb) orally once daily. The dose may be reduced by 0.5 mg/kg (0.23 mg/lb) increments to a minimum of 0.5 mg/kg (0.23 mg/lb) orally once daily to manage SEMINTRA-induced hypotension. SEMINTRA can be administered directly into the mouth, or next to or on top of a small amount of food. Do not mix into food.

SEMINTRA should be administered using the dosing syringe provided in the package. The dosing syringe fits onto the bottle and has 0.1 mL incremental marks. The dose should be rounded to the nearest 0.1 mL. After administration close the bottle tightly with the cap. Rinse the dosing syringe with water and let air dry.

If the cat vomits within 30 minutes of dosing, the cat may be re-dosed.
Information for Cat Owners

Always provide the Client Information Sheet with each prescription and review it with the cat owner. Advise cat owners that adverse reactions can occur with use of SEMINTRA. The most common adverse reactions reported during the field studies included vomiting, diarrhea, lethargy, weight loss, anemia and dehydration.
CONTRAINDICATIONS

Do not use in cats with a known hypersensitivity to telmisartan.
HUMAN WARNINGS

Not for human use. Keep out of reach of children.

SEMINTRA is an angiotensin II antagonist/angiotensin receptor blocker (ARB). Pregnant women should avoid contact with SEMINTRA because substances that act on the renin-angiotensin-aldosterone system (RAAS) such as angiotensin receptor blockers (ARBs) can cause fetal and neonatal morbidity and death during pregnancy in humans.
PRECAUTIONS

SEMINTRA has not been evaluated in cats with systolic blood pressure >200 mm Hg.

SEMINTRA can cause mild anemia or non-regenerative anemia. Cats should be monitored for anemia when initiating treatment with SEMINTRA.

SEMINTRA may cause inappetence and weight loss in some cats. Cats should be monitored for weight loss when initiating treatment with SEMINTRA. Use with caution in cats with a history of vomiting, inappetence or weight loss.

The safe use of SEMINTRA in cats with hepatic disease has not been evaluated. SEMINTRA is metabolized by the liver.

The safe use of SEMINTRA has not been evaluated in cats less than 9 months of age.

The safe use of SEMINTRA has not been evaluated in cats that are pregnant, lactating, or intended for breeding. See Human Warnings.

The safe use with other anti-hypertensive medications has not been evaluated.

28-day Field Effectiveness Study
Safety was evaluated in a 28-day field study in 288 cats (192 SEMINTRA group cats, 96 control group cats) that received at least one dose of study drug. The control product was a vehicle control without telmisartan. Cats enrolled in the study had a median age of 14 years (7-20 years), and weighed 1.93-11.4 kg. SEMINTRA was administered orally at 1.5 mg/kg twice daily for 14 days, then 2 mg/kg once daily until study end; the control was administered at a volume equivalent to SEMINTRA. One hundred fourteen (59.4%) SEMINTRA group cats and 42 (43.8%) control group cats had at least one adverse reaction. Adverse reactions that occurred in at least 5% of either treatment group are presented in Table 1 below.

Table 1 Adverse Reactions in the 28-Day Field Study

Clinical Sign	SEMINTRA N=192	Control N=96
Vomiting	46 (24.0%)	14 (14.6%)
Diarrhea	18 (9.4%)	4 (4.2%)
Lethargy	13 (6.8%)	3 (3.1%)
Weight loss	13 (6.8%)	5 (5.2%)
Decreased appetite/inappetence	13 (6.8%)	7 (7.3%)
Non-regenerative anemia	11 (5.7%)	2 (2.1%)
Dehydration	10 (5.2%)	4 (4.2%)
Retinal lesions (target organ damage)	4 (2.1%)	6 (6.3%)

Additional adverse reactions that occurred in <5% of the SEMINTRA group included (in order of decreasing frequency): anorexia, gagging, arrhythmia, cough, heart murmur, and regenerative anemia. Additional adverse reactions representing 2-5% of the control group included azotemia, not drinking and renal failure.

Seven cats (five SEMINTRA and two control) either died or were euthanized during the study. None of the SEMINTRA group deaths were considered related to treatment.

5-month Field Effectiveness and Safety Study
The long-term safety of SEMINTRA was evaluated in an open label, 5 month field effectiveness and safety study in 107 cats that received at least one dose of SEMINTRA. Cats enrolled in the study had a mean age of 14.1 years (7-20 years) and weighed 1.92-11.4 kg. SEMINTRA was administered orally at 2 mg/kg once daily. Ninety-four cats (87.9%) had at least one adverse reaction during the study. Adverse reactions that occurred in at least 5% of cats are presented in Table 2 below.

Table 2 Adverse Reactions in the 5-Month Study

Clinical Sign	SEMINTRA N=107
Weight loss	37 (34.6%)
Vomiting	32 (29.9%)
Dehydration	18 (16.8%)
Non-regenerative anemia	17 (15.8%)
Anorexia	14 (13.1%)
Diarrhea	12 (11.2%)
Lethargy	12 (11.2%)
Decreased appetite/inappetence	11 (10.3%)
Heart murmur	10 (9.3%)
Death, Euthanasia, Found dead	9 (8.4%)
Cough	8 (7.5%)
Retinal lesions (target organ damage)	6 (5.6%)

Adverse reactions representing <5% of the study population were (in order of decreasing frequency): elevated liver enzymes, renal failure, tachycardia, arrhythmia, azotemia, depression, loose stool, constipation, gagging, hypotension, regenerative anemia, renal insufficiency, and vocalization.

Nine cats died or were euthanized during the study. Three cats had progressive chronic kidney disease that may have been affected by telmisartan treatment, concurrent disease, or inadequate control of hypertension. The other six cats died of causes unrelated to treatment (e.g. neoplasia).

To report suspected adverse drug events, for technical assistance, or to obtain a copy of the Safety Data Sheet (SDS), contact Boehringer Ingelheim Vetmedica, Inc. at 1-866-638-2226. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or at http://www.fda.gov/AnimalVeterinary/SafetyHealth.

CLINICAL PHARMACOLOGY

Telmisartan is a selective angiotensin II subtype AT1 receptor blocker, with no relevant affinity for other receptors in general receptor-binding assays. Telmisartan is metabolized to the 1-O-acylglucuronide of telmisartan, which, in cats treated for 6 days at 1 mg/kg, was shown to be present in the plasma at levels approximately 21% of that of unchanged parent compound.

Following an oral dose of 1 mg/kg telmisartan once daily for five days, the time to reach mean peak plasma concentration (Tmax) was 21 minutes and 32 minutes for fasted and fed cats, respectively. There was a higher systemic exposure to telmisartan in the fasted cats based on the maximum concentration (Cmax) and area under the concentration vs time curve (AUC). The mean terminal elimination half-life was approximately 8 hours. The mean systemic exposure of telmisartan (Cmax and AUC) was approximately 60% lower for female cats compared to male cats. However, dose adjustment for female cats is not necessary. An increase in dose from 1 to 5 mg/kg once daily resulted in a greater than proportional increase in telmisartan exposure. There could be low to moderate accumulation of drug upon repeated once daily or twice daily administrations of 1.5-2 mg/kg.

EFFECTIVENESS

Effectiveness was demonstrated in a 28-day multi-center, controlled, randomized and masked field study in client-owned cats with hypertension, and in an open-label 5-month field study.

28-Day Field Study
In the 28-day study, 288 cats with hypertension (systolic blood pressure [SBP] 160-200 mmHg) were enrolled in the study and randomized to treatment with SEMINTRA (telmisartan oral solution) (n=192) or vehicle control (n=96). The study population included cats with hypertension associated with chronic kidney disease or controlled hyperthyroidism, or idiopathic hypertension. The per protocol population for effectiveness was 141 SEMINTRA treated cats and 79 control cats. SEMINTRA was administered orally at 1.5 mg/kg twice daily for 14 days, then 2 mg/kg once daily until study end; the vehicle control was administered at a mL/kg volume equivalent to SEMINTRA. The two primary variables for effectiveness were comparison of the SEMINTRA and control group mean SBP (mSBP) from baseline to Day 14, and a decrease in mSBP >20 mmHg in the SEMINTRA group from baseline to Day 28. Cats with SBP >180 mmHg at Days 14 or 28 were rescued and removed from the study. There was a statistically significant difference between the mSBP for the SEMINTRA group compared to the control group at Day 14 (p=0.0005). At Day 14 the SEMINTRA group mSBP decreased by 23.2 mmHg, and the control group mSBP decreased by 7.3 mmHg. At Day 28, the SEMINTRA group mSBP decreased 23.9 mmHg compared to baseline.

5-Month Field Study
One hundred-seven cats from the SEMINTRA group that had successfully completed the 28-day study were enrolled in a 5-month open-label study. At the beginning of the 5-month study most cats were administered SEMINTRA at 2 mg/kg once daily. Cats that experienced hypotension (defined as SBP <120 mmHg) at 2 mg/kg once daily could have the SEMINTRA dose reduced to 1 mg/kg once daily. Cats that experienced hypotension at 1 mg/kg once daily could have the SEMINTRA dose reduced again to 0.5 mg/kg once daily. Cats were evaluated for SBP, target organ damage (TOD; primarily assessed by retinal photographs), clinical pathology and adverse reactions. SBP was measured on Days 28, 56, 98, 140 and 182 and retinal photographs and clinical pathology were collected on Days 28, 98 and 182. Seventy-three (68.2%) cats completed the study (Day 182), 8 cats were removed for hypertension (SBP >180 mmHg), 2 cats were removed for hypotension, 10 cats were removed by the owner or for owner non-compliance, 8 cats were removed for new or worsening TOD, and 6 cats were removed for adverse reactions unrelated to TOD. Twenty-six cats had dose reductions to 1 mg/kg once daily to manage hypotension. Of these 26 cats, 10 had an additional dose reduction to 0.5 mg/kg once daily.

Table 3 Distribution of Cats by SBP Range and Study Day in the 5-Month Study a

SBP Range (mm Hg)

Baseline

N=107

n (%)

Day 28

N=107

n (%)

Day 56

N=102

n (%)

Day 98

N=91

n (%)

Day 140

N=80

n (%)

Day 182

N=69

n (%)

< 150

(0%)

(54.2%)

(53.9%)

(67%)

(55%)

(59.4%)

> 150–160

(3.7%)

(17.8%)

(18.6%)

(18.7%)

(26.2%)

(23.2%)

> 160–170

(35.5%)

(16.8%)

(13.7%)

(11%)

(15%)

(10.1%)

> 170–180

(26.2%)

(11.2%)

(9.8%)

(2.2%)

(3.8%)

(5.8%)

> 180

(34.6%)

(0%)

(3.9%)

(1.1%)

(0%)

(1.5%)

a SBP obtained at unscheduled visits are not represented. Cats that were removed for missing >3 doses prior to SBP measurement are not included.

The most commonly used concomitant treatments during the 5-month study included (in order of frequency) antibiotics, anesthesia/sedatives/analgesia, nutritional supplements, vaccines, prescription diets, antiparasitics, thyroid treatment, antiemetics and fluid therapy.

ANIMAL SAFETY

In a six-month target animal safety study, healthy cats 9 to 13 months old were administered telmisartan orally, once daily at 0, 1, 3, or 5 mg/kg body weight.

Control cats (0 mg/kg) received saline at a volume equal to the 5 mg/kg dose. There were eight cats per group (4 males, 4 females).

All cats survived the study, and there were no telmisartan-related effects on clinical observations, physical examination, body weight, ophthalmic examination, coagulation parameters, urinalysis, and gross necropsy.

Blood pressure was lower in the groups administered telmisartan compared to the control group. Blood pressure was lower starting at week 4 in the 1 mg/kg group, at week 2 in the 3 mg/kg group, and during the first week in the 5 mg/kg group. This is an expected pharmacologic effect of telmisartan. Food consumption in the 3 and 5 mg/kg group cats was lower than that of the control group.

Telmisartan-related effects on hematology parameters included lower red blood cell count, hemoglobin, hematocrit, and reticulocytes in the 3 and 5 mg/kg group cats. One 5 mg/kg group cat also had mild generalized depletion of the hematopoietic cells on bone marrow histology. In some 5 mg/kg group cats, decreases in red blood cell precursors on bone marrow cytology were considered telmisartan-related.

Blood urea nitrogen (BUN) was statistically significantly higher for the 3 mg/kg group at weeks 12 and 16, and for the 5 mg/kg group at weeks 2, 4, 7, 12, 16, 20, and 25, when compared to the control group. There were no clinical signs associated with the changes in BUN.

There was a telmisartan-related effect on lower heart weight in the 3 and 5 mg/kg groups compared to the control group, but the histopathology was normal in all treated cats. On kidney histology, there was minimal to mild hypertrophy of the juxtaglomerular apparatus in the 1, 3, and 5 mg/kg group cats. Kidney histology was normal in control group cats.
STORAGE CONDITIONS

Store at or below 25°C (77°F) with excursions permitted up to 40°C (104°F). Once the bottle is opened, use the contents within six months.
HOW SUPPLIED

SEMINTRA (telmisartan oral solution), 10 mg/mL, 35 mL fill volume, is supplied in a 45 mL plastic bottle with a dosing syringe. NDC: 0010-4492-01
SPL UNCLASSIFIED SECTION

NADA 141-501, Approved by FDA

Manufactured for:
Boehringer Ingelheim Vetmedica, Inc.
St. Joseph, MO 64506 U.S.A.

Made in Spain

Semintra is a registered trademark of Boehringer Ingelheim Vetmedica GmbH, used under license.

© 2018 Boehringer Ingelheim Vetmedica, Inc. All Rights Reserved.

Revised 03/2018

449201-00

CLIENT INFORMATION SHEET

The Client Information Sheet contains important information about SEMINTRA. You should read this information before you start giving SEMINTRA and review it each time the prescription is refilled as there may be new information. This sheet is provided only as a summary and does not take the place of instructions from your veterinarian. Talk with your veterinarian if you do not understand any of this information or if you want to know more about SEMINTRA.

What is SEMINTRA?
SEMINTRA (telmisartan oral solution) is used to control high blood pressure in cats.

What should I tell my veterinarian about my cat before starting SEMINTRA?

Tell your veterinarian about other medications your pet is taking, including prescription drugs, over the counter drugs, heartworm preventatives, flea & tick medications, and vitamins and supplements, including herbal medications.
Tell your veterinarian if your cat is pregnant, nursing, or you intend to breed him/her.
Tell your veterinarian if your cat has any other serious health conditions, anemia (low red blood cell count), vomiting or diarrhea, decreased appetite or weight loss.

Talk to your veterinarian about:

How often your veterinarian should recheck your cat’s blood pressure while taking SEMINTRA
The risks and benefits of taking SEMINTRA

What are some of the possible side effects of SEMINTRA?
Like all drugs, SEMINTRA may cause side effects, even at the prescribed dose. Serious side effects can occur, with or without warning, and in some situations result in death. Contact your veterinarian immediately if your cat develops a medical problem or side effect while taking SEMINTRA.

The most common side effects which can occur with SEMINTRA include vomiting, diarrhea, lethargy, weight loss, anemia (low red blood cell count) and dehydration.

There are other side effects which may occur. For a complete list, ask your veterinarian.

To report a suspected adverse reaction (side effects) contact Boehringer Ingelheim Vetmedica Inc. at 1-866-638-2226.

How do I give SEMINTRA to my cat?
SEMINTRA should be given to your cat in their mouth (orally) or next to or on top of a small amount of food. Do not mix into food.

Follow your veterinarian’s instructions for how much and how often to give SEMINTRA.

Give SEMINTRA using the dosing syringe provided in the package. The dosing syringe fits into the bottle opening and has 0.1 mL marks to use for measuring the dose.

Remove the cap from the bottle and gently push the end of the dosing syringe into the bottle opening.

Turn the bottle/syringe upside down.

Pull the plunger out and fill the dosing syringe to the dose prescribed by your veterinarian.

Turn the bottle upright and remove the dosing syringe from the bottle.

Put the end of the dosing syringe into your cat’s mouth, and push the plunger to give the dose…

Or put the dose next to or on top a small amount of food. Do not mix into food. If SEMINTRA is put onto food, make sure your cat eats the food and the entire dose.

If your cat vomits within 30 minutes of giving the SEMINTRA (telmisartan oral solution) dose, your cat can be given the same dose again. If your cat vomits more than 30 minutes after giving SEMINTRA, do not give SEMINTRA again until the next scheduled dose.

After dosing, replace the cap on the bottle and close tightly. Rinse the SEMINTRA dosing syringe with water and let air dry.

What should I do if my cat gets more than the prescribed amount of SEMINTRA?
Your cat may develop low blood pressure or other side effects. Contact your veterinarian immediately.

Human Warnings:
SEMINTRA is not for use in humans.

You should keep SEMINTRA in a secure storage area out of the reach of children.

Pregnant women should avoid contact with SEMINTRA, because other similar drugs have been found to harm the unborn baby during pregnancy.

If SEMINTRA is accidentally ingested, contact a physician. It is important to show the treating physician a copy of the package insert, label, or client information sheet. SEMINTRA is an angiotensin II receptor blocker.

This client information sheet contains a summary of important information about SEMINTRA. For more detailed information about SEMINTRA, talk with your veterinarian.

Storage Statement: SEMINTRA (telmisartan oral solution) can be stored at 77°F and can be transported for short periods up to 104°F. Once the bottle is opened, use the contents within six months.

Revised 03/2018

Principal Display Panel - 35 mL Container Label

NDC: 0010-4492-01

Semintra®
(telmisartan oral solution)
10 mg/mL

For oral use in cats only
Angiotensin II Receptor Blocker

Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.
Principal Display Panel - 35 mL Display Carton

NDC: 0010-4492-01

Semintra®
(telmisartan oral solution)
10 mg/mL

For oral use in cats only
Angiotensin II Receptor Blocker

Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

NADA 141-501, Approved by FDA

INGREDIENTS AND APPEARANCE

SEMINTRA
telmisartan solution

Product Information
Product Type	PRESCRIPTION ANIMAL DRUG	Item Code (Source)	NDC: 0010-4492
Route of Administration	ORAL

Ingredient Name	Basis of Strength	Strength
Active Ingredient/Active Moiety
TELMISARTAN (UNII: U5SYW473RQ) (TELMISARTAN - UNII:U5SYW473RQ)	TELMISARTAN	10 mg in 1 mL

#	Item Code	Package Description
Packaging
1	NDC: 0010-4492-01	1 in 1 CARTON
1		35 mL in 1 BOTTLE, PLASTIC

Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Marketing Information
NADA	NADA141501	09/18/2018

Labeler - Boehringer Ingelheim Vetmedica, Inc. (007134091)

Trademark Results [Semintra]

Mark Image Registration \| Serial	Company Trademark Application Date
SEMINTRA 87853684 5600965 Live/Registered	Boehringer Ingelheim Vetmedica GmbH 2018-03-28
SEMINTRA 87276048 not registered Dead/Abandoned	Boehringer Ingelheim Vetmedica GmbH 2016-12-21
SEMINTRA 79133607 4483202 Live/Registered	Boehringer Ingelheim Vetmedica GmbH 2013-05-14
SEMINTRA 79115035 4290764 Dead/Cancelled	Boehringer Ingelheim Vetmedica GmbH 2012-06-04
SEMINTRA 76702353 3921451 Dead/Cancelled	Boeheringer Ingelheim Vetmedica GmbH 2010-04-02