Tenapanor - Indication, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Introduction

Tenapanor is a medicine that is used to treat IBS-C also known as irritable bowel syndrome with constipation. IBS-C is a disorder that results in stomach discomfort or cramps, bloating, and irregular or troublesome bowel movements. The drug Tenapanor belongs to a group of drugs known as sodium/hydrogen exchanger (NHE3) inhibitors. The drug acts by speeding the passage of waste and food from the stomach and intestines.

Information for the Patients:

How Should This Medication Be Taken?

Tenapanor is available as an oral tablet. It is taken two times a day. One right before breakfast and the other right before dinner. Tenapanor should be taken every day at around the exact same time. Ask the doctor or chemist to clarify any instructions on the label of the prescription that the patient is unsure about following. Tenapanor must be taken as prescribed. It should never be taken in larger or fewer amounts or more frequently than directed by the doctor.

Tenapanor manages IBS-C symptoms but does not treat the condition. The constipation symptoms could get better in a week, but the stomach discomfort can take a little longer to heal. Tenapanor should be taken even if the patient is feeling fine. The drug should never be stopped without seeking medical advice.

What Specific Safety Measures Should Be Taken?

Prior to Ingestion of Tenapanor:

• In the event that a patient is allergic to Tenapanor, any other medications, or any of the ingredients in Tenapanor tablets, they should inform their doctor and chemist right away. For a list of the components, consult the medication guide or speak with the chemist.

• The patient should inform the physician and chemist about more medications, including those on prescription, vitamins, over-the-counter medications, herbal items, and nutritional supplements they are currently using or intend to take. The dosage of the drugs may need to be changed, or the healthcare provider may need to watch for adverse effects closely.

• If the stomach or bowels are blocked in any way, let the doctor know. Most likely, the doctor will advise against using Tenapanor.

• Inform the doctor whether the patient has any additional medical conditions presently or in previous years.

• If the patient is expecting, wants to get pregnant, or is nursing a baby, they should inform the healthcare worker. If a patient is taking Tenapanor and becomes pregnant, they must inform the doctor as soon as possible.

How Is the Medicine Stored and Disposed Of?

The medicine must be kept in the original and tightly secured container. It is important to store it in a location inaccessible to children. The drug should not be kept in a location where there is excessive heat and moisture, especially in the bathroom. If a desiccant (drying agent) has been supplied, do not remove it from the bottle. All the medical supplies must be stored in a place that is out of children’s reach and as well as sight. Medicines like eye drops, inhalers, patches, eye drops, creams, and pill reminders can be opened easily by children, and hence extra measures should be taken to keep them away from children. Safety caps must be secured immediately after using the medication.

Prescriptions that have not been used must be properly disposed of to keep dogs, children, and other people from consuming them. The medication should, however, never be discarded in the bathroom. Instead, the best way to dispose of the medications is to use a drug take-back program. More information regarding the take-back program can be provided by the chemist or the recycling department of the city. One can also visit the FDA (Food and Drug Administration) website on safe disposal of medicines to find out more about the take-back program.

What Are the Adverse Effects of the Drug?

The drug, Tenapanor, can have side effects on the patient. The doctor needs to be informed at the earliest in case the side effects like dizziness, bloating of the stomach, abdominal pain, and diarrhea do not disappear. The healthcare provider needs to be informed immediately in case the person suffers from severe diarrhea.

Overdosing:

In case of overdosing, medical help should be taken immediately. Symptoms of overdosing are diarrhea, severe thirst, eyes are sunken, rapid heartbeat, dry skin and mouth, and reduced urine flow. If the overdose victim collapses, has a seizure, has difficulty in breathing, or does not wake up or open their eyes, they must be admitted without any delay.

Information for the Doctors:

Drug Indication and its Usage:

Tenapanor is prescribed for individuals with IBS-C (irritable bowel syndrome with constipation).

Contraindications for the Drug:

• Patients under the age of six because they incur the risk of developing significant dehydration.

• People with a confirmed or suspected diagnosis of mechanical gastrointestinal blockage.

Drug Dosage and Its Administration:

Adults should take 50 mg of Tenapanor twice a day or as directed by the healthcare worker.

It has the oral mode of administration and should be taken prior to meals both in the morning (first meal of the day) and at night. The missed dose should be skipped and not taken. The next dose should be taken as per the scheduled time. To compensate for the missed dose, two doses of the drug should never be taken.

Drug Form and Its Strength:

The drug Tenapanor is available in the form of tablets. The strength of the drug is 50 milligrams (mg). The tablet is oval in shape, and the color of the drug is white to off-white. The numbers 5791 and 50 are debossed on either side of the tablet.

Drug Storage:

The medicine is stored in a dry place away from moisture at a temperature of between 68 Fahrenheit and 77 Fahrenheit (20 degrees Celsius and 25 degrees Celsius) at room temperature.

Precautions:

• Pediatric Patients Are at Risk for Serious Dehydration - Tenapanor is not recommended for patients under the age of six. Tenapanor has not been proven to be safe or effective in individuals who are under 18 years old. According to trial studies, when Tenapanor was administered orally to young rats who were one week or less than one week old (which is the same as a two-year-old human being), they lost weight and died from dehydration. Data on older juvenile rats are not available (human age ranging from 2 years to 12 years). Avoid using Tenapanor in patients 12 years of age and younger due to the mortality in younger rats and a shortage of effectiveness and clinical safety evidence in pediatric patients.

• Diarrhea - In two of the randomized, double-blind, placebo-controlled studies of IBS-C, diarrhea was the most typical adverse effect noted. 2.5 percent of the patients who were being treated with Tenapanor reported suffering from severe diarrhea. Drug dosing should be suspended if severe diarrhea occurs. The patient must be hydrated immediately and simultaneously.

Adverse Reactions:

The adverse reactions were gathered based on the clinical trial studies. In two randomized, double-blind, placebo-controlled clinical studies (Trial 1 and Trial 2), 1203 adult patients with the diseased condition, IBS-C provided data that were used to compile the safety data. The trial duration was 52 weeks. Randomly chosen patients were either given a placebo or Tenapanor 50 mg two times a day. The most common adverse reactions reported were severe diarrhea which sometimes led to drug discontinuation. A few people also complained about the odd gastrointestinal sounds and bleeding from the rectum. Also, a few people with type 2 diabetes mellitus and chronic renal failure reported hyperkalemia (only three such cases were reported, out of which two were being treated with Tenapanor and one of the patients was on placebo).

Drug Use in Specific Population:

Pregnancy - The drug, Tenapanor is orally administered. It is absorbed weakly by the body and hence is not determined in the plasma concentration. Hence, the fetus is not harmed if it is exposed to the drug. As per a study on a very small population of pregnant women, it was found that there is no drug-related risk for serious birth abnormalities, miscarriage, or unfavorable maternal or fetal outcomes. Tenapanor was used in a reproduction study on pregnant rabbits and rats, and no harmful effects were seen on the fetus. The rats were given a dose that was 0.1 times the maximum dose that is advised safe for humans, and rabbits were given a dose that was 8.8 times the maximum dose advised safe for human use.

Animal Data on Pregnancy:

• Organogenesis - During a research study on embryonic, fetal development in rats, Tenapanor was given orally to pregnant rats at the time of organogenesis. The doses administered were of 1, 10, and 30 mg/kg/day. The pregnant rats did not tolerate the Tenapanor dosages of 10 and 30 mg/kg/day and showed a loss in body weight along with mortality and morbidity. Thus, the fetuses of the 10 and 30 mg/kg dosage group animals were terminated early, and neither intrauterine parameters nor fetal morphology was assessed. Rats at 1 mg/kg/day (about 0.1 times the maximum dose advised for humans) and rabbits up to 45 mg/kg/day (roughly 8.8 times the maximum dose advised for humans, depending on body surface area) showed no significant fetal effects.

• Prenatal and Postnatal Development - Tenapanor exhibited no impact on prenatal or postnatal development in a mouse pre and postnatal development study at dosages up to 200 mg/kg/day (about 9.7 times the maximum advised human dose depending on body surface area).

• Lactation - No information is available regarding the effect of Tenapanor on infants who are breastfed or on milk production. Tenapanor’s presence is also not detected either in animal or human milk. Following oral dosing, Tenapanor is only weakly absorbed systemically, with plasma values less than the limit of detection (less than 0.5 ng/mL).

2. Pediatric Population - Tenapanor is not recommended for patients under the age of 12. Tenapanor has not been proven to be safe or effective in individuals under the age of 18.

Animal Data on Pediatric Population:

• Tenapanor was given to neonatal rats (post-natal day (PND) 5) in a 21-day oral dosage range finding toxicity investigation to juvenile rats at doses of 5 and 10 mg/kg/day. Male and female pups did not tolerate Tenapanor, and the trial was stopped on PND 16 because of deaths and decreased body weight (33 percent loss in males in the 10 mg/kg/day group and a reduction of 24 percent to 29 percent in females at the relevant dosage groups).

• In another study related to the toxicity of the drug, lower ovarian, thymus, and/or spleen weights were seen at dosages of 0.5, 2.5, and 5 mg/kg/day. Males and females neonatal pups in the 0.5, 2.5, and 5 mg/kg/day dosing groups experienced Tenapanor-related gastrointestinal distension, microscopic bone findings of eroded bone, reduced bone in the femorotibial joint or sternum, and increased osteoclasts were seen.

• Geriatric Population - 100 (eight percent) of the 1203 individuals who participated in placebo-controlled clinical studies of Tenapanor were of 65 years or older. Elderly patients and younger patients did not generally vary in terms of safety or efficacy, although it is possible that certain older patients may be more sensitive than others.

Clinical Pharmacology

Mechanism of Action

• An antiporter found on the apical portion of the colon and small intestine that is principally in charge of absorbing dietary sodium is called the sodium-hydrogen exchanger 3 (NHE3). Tenapanor is an inhibitor of NHE3 which functions locally. Its primary metabolite, M1, does not seem active against NHE3, according to animal and in vitro investigations. Tenapanor decreases salt absorption from the colon and small intestine by blocking NHE3 on the apical part of the enterocytes. This causes an increase in water secretion into the intestinal lumen, which speeds up intestinal transit time and results in softer stool consistency. In animal models, Tenapanor has also been found to lessen stomach discomfort by lowering visceral hypersensitivity and intestinal permeability. Tenapanor decreased visceral hyperalgesia and restored normal colonic sensory neuronal excitability in a rat model of colonic hypersensitivity.

Pharmacodynamics

• Cardiac Electrophysiology - There were no clinically significant effects on the QTc (QT corrected for heart rate) interval at a dose that was three times the typical maximum exposure to M1 at that time.

• Food Effect - When Tenapanor is taken immediately before a meal (5 to 10 minutes), it increases the excretion of sodium via stool when compared to drug consumption in a fasting state or after having food

Pharmacokinetics

• Absorption - Upon repeated oral administration of the drug two times a day, minimal absorption takes place. When plasma concentration for the drug was evaluated in healthy individuals who were taking 50 mg of Tenapanor twice daily, it was found that the medicine was undetectable in the plasma. As a result, it was unable to establish common pharmacokinetic parameters, including half-life (t1/2), maximum concentration (Cmax), and area under the curve (AUC).

• Distribution - Tenapanor and its main metabolite, M1, had 99 % and 97 % plasma protein binding, respectively, in vitro.

Elimination

• Metabolism - Metabolism of Tenapanor is done by CYP3A4 or CYP3A5 enzyme. The main metabolite is M1 which is detected in the plasma in a very less quantity. In healthy individuals, the Cmax of M1 is around 13 ng/mL (nanogram per milliliter) after a single dosage of Tenapanor 50 mg and 15 ng/mL at a steady state after several doses of Tenapanor 50 mg twice daily.

• Excretion - After giving healthy patients a single dosage of 15 mg radiolabeled 14C Tenapanor, the majority of the radioactive substance (70 percent) was eliminated in the feces after 120 hours, and after 240 hours, the excreted radiolabeled drug percentage was 79. Within 144 hours after drug administration, 65 percent of medicine was excreted as the parent drug. Urine testing revealed that nine percent of the injected dosage was recovered, mostly as metabolites. Within 144 hours of the treatment, M1 is unchanged and eliminated in the urine, making up 1.5 percent of the dose.

Non-Clinical Toxicology

• Carcinogenesis - Tenapanor's ability to cause cancer was evaluated in two separate studies: a 2-year rat study and a six-month carcinogenicity investigation in Tg rasH2 mice.In male mice, oral dosages up to 100 mg/kg/day (based on the surface area of the body, it is about 4.5 times the recommended safe dosage for humans), and in female mice, oral dosages up to 800 mg/kg/day (based on the surface area of the body it is about 39 times the recommended safe dosage for humans), Tenapanor was found to be not tumorigenic. As a collective population of male and female rats, Tenapanor was found to be non-tumorigenic for doses up to 5 mg/kg/day. Based on the body surface area, it is about 0.5 times the suggested safety human dose. In Tg rasH2 mice, the main metabolite of Tenapanor, M1, was not tumorigenic at oral dosages up to 165 mg/kg/day, which is about eight times the highest dose that is safe for humans (on the basis of the surface area of the body).

• Mutagenesis - Tenapanor was found not to be genotoxic when evaluated in vitro for bacterial reverse mutation. It was also found to be non-genotoxic when evaluated for micronucleus in mice and rats in vivo.

• Fertility Impairment - Tenapanor exhibited no impact on reproductive health and fertility in male rats when provided oral dosing of 10 mg/kg/day. Based on the body surface area, it was roughly around 0.97 times the permitted human dosing. Female mice exhibited no impact on reproductive health for oral dosing up to 50 mg/kg/day, which is roughly around 2.4 times the permitted human dosing.

Clinical Trial Study and Drug Efficacy

Two double-blind, placebo-controlled, randomized, multicenter studies in adult patients were conducted to determine the effectiveness of Tenapanor for the treatment of IBS-C. Trail 1 had 620 patients, and Trial 2 had 606 patients. The age of the subjects who participated in the study was 46 years. Out of all the people enrolled, 80 percent were females. In these clinical trials, Tenapanor was given prior to breakfast or the morning’s first meal, as well as right before dinner. Through the first 12 weeks of therapy, the study format was identical for both trials; however, following that, Trial 1 continued the study for another 14 weeks (for a total of 26 weeks of double-blind study), whereas Trial 2 consisted of a four-week randomized withdrawal (RW) phase.

The Inclusion Criteria for the Study Included the Following:

• The average score for abdominal pain should be three. A score of 10 indicated extreme pain in the abdomen, whereas 0 indicated no pain.

• The count of complete spontaneous bowel movements (CSBM) should be less than three.

• The count of (SBM) spontaneous bowel movements (bowel movements without using laxatives) should be less than or equal to five.

Drug Efficacy

• By the first week, improvements from baseline were seen in the mean weekly CSBMs and abdominal discomfort in both studies where the patients were treated with Tenapanor, and these positive effects persisted through the completion of the course of therapy.

• In Trial 2, as the patients were re-randomized from placebo to Tenapanor, they showed improvement as the abdominal pain decreased and CSBM frequency increased. Patients who were already being treated with Tenapanor continued to show improved results. Patients who were treated with Tenapanor but were re-randomized to placebo showed an increase in abdominal pain, but it remained better than the baseline.

• The overall result was satisfactory for the treatment of IBS-C.