Aliskiren Hemifumarate

For the treatment of essential hypertension in adults, the standard starting dose of Aliskiren Hemifumarate is 150 mg taken orally once daily. Healthcare providers will monitor the patient's blood pressure response over the course of two weeks. If the blood pressure is not adequately controlled at the 150 mg level, the dose may be increased to a maximum of 300 mg once daily. Doses higher than 300 mg have not been shown to provide additional blood pressure lowering benefits but do significantly increase the risk of adverse effects, particularly gastrointestinal issues like diarrhea.

Aliskiren is approved for use in pediatric patients aged 6 years and older who weigh at least 20 kg. For children and adolescents, the dosage is often determined by body weight:

• Children 20 kg to <50 kg: The starting dose and titration schedule are determined by the specialist, often starting at lower increments than adults.
• Children ≥50 kg: The starting dose is typically 150 mg once daily, similar to the adult regimen.

Note: Aliskiren is strictly contraindicated in pediatric patients less than 2 years of age due to the risk of significant kidney damage and potential toxicity related to the immature development of the RAAS and renal transporters in infants.

Renal Impairment

In patients with mild to moderate renal impairment (Creatinine Clearance ≥ 30 mL/min), no initial dosage adjustment is usually required. However, Aliskiren should be used with extreme caution in patients with severe renal impairment (CrCl < 30 mL/min). Clinical monitoring of serum potassium and creatinine levels is mandatory in these populations.

Hepatic Impairment

No initial dosage adjustment is required for patients with mild, moderate, or severe hepatic impairment. Because Aliskiren is primarily excreted unchanged in the feces via the bile, liver enzyme dysfunction does not significantly alter the drug's clearance.

Elderly Patients

No specific starting dose adjustment is required for elderly patients (65 years and older). However, because older adults are more likely to have decreased renal function or be taking multiple medications (polypharmacy), healthcare providers should monitor blood pressure and kidney function more frequently.

To ensure the medication works effectively and provides consistent blood pressure control, patients should follow these specific administration guidelines:

• Consistency with Food: Aliskiren should be taken the same way every day—either always with food or always without food. Because high-fat meals significantly reduce absorption, changing how you take the medication relative to meals can cause your blood pressure to fluctuate.
• Swallow Whole: Tablets should be swallowed whole with water. Do not crush, chew, or split the tablets unless specifically instructed by your pharmacist or doctor.
• Time of Day: It is best to take the dose at the same time each day (e.g., every morning) to maintain steady levels in the bloodstream.
• Storage: Store the medication at room temperature (68°F to 77°F or 20°C to 25°C) in a dry place. Keep the tablets in their original container or blister pack to protect them from moisture.

If you miss a dose of Aliskiren Hemifumarate, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and resume your regular schedule. Do not take two doses at once to "make up" for a missed one, as this increases the risk of severe hypotension (low blood pressure).

Signs of an Aliskiren overdose may include severe hypotension (dizziness, fainting, blurred vision) and electrolyte imbalances. If an overdose is suspected, contact a poison control center or seek emergency medical attention immediately. Treatment is primarily supportive, involving intravenous fluids to maintain blood pressure and monitoring of kidney function.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking the medication without medical guidance, as sudden discontinuation can lead to a rapid rise in blood pressure.

The most frequently reported side effect associated with Aliskiren Hemifumarate is diarrhea. This gastrointestinal symptom is dose-related, occurring more frequently at the 300 mg dose than the 150 mg dose. Patients describe it as loose, watery stools that typically begin within the first few weeks of therapy. While usually mild, it can be bothersome. Other common experiences include dizziness, particularly when moving from a sitting to a standing position (orthostatic hypotension), and a mild headache.

• Cough: While Aliskiren is less likely to cause a dry, persistent cough than ACE inhibitors, it still occurs in a small percentage of patients (about 1.1%).
• Flu-like Symptoms: Some patients report fatigue, nasopharyngitis (sore throat/runny nose), or upper respiratory tract infections.
• Back Pain: Muscle or skeletal discomfort has been noted in clinical trials.
• Rash: Mild skin reactions or itching may occur.

• Hyperkalemia: An abnormally high level of potassium in the blood. This is more common in patients with diabetes, kidney disease, or those taking potassium supplements.
• Severe Hypotension: Especially in patients who are volume-depleted (e.g., those on high-dose diuretics).
• Renal Impairment: Changes in kidney function, marked by increases in serum creatinine.

> Warning: Stop taking Aliskiren Hemifumarate and call your doctor immediately if you experience any of these serious symptoms.

• Angioedema: This is a life-threatening allergic reaction involving swelling of the face, lips, tongue, and throat. It can cause difficulty breathing or swallowing. This reaction can occur at any time during treatment, even if you have taken the drug safely for months.
• Anaphylactic Reactions: Severe systemic allergic reactions including hives, rapid pulse, and feeling like you might pass out.
• Severe Hyperkalemia: Symptoms include muscle weakness, heart palpitations (irregular heartbeats), and tingling in the extremities. If left untreated, high potassium can cause cardiac arrest.
• Acute Renal Failure: A sudden drop in kidney function. Symptoms include decreased urination, swelling in the legs or ankles, and shortness of breath.

With prolonged use, the primary concern is the impact on renal (kidney) health and electrolyte balance. Long-term therapy requires periodic blood tests to ensure that the kidneys are filtering correctly and that potassium levels remain within a safe range. There is no evidence that Aliskiren causes cumulative toxicity, but its effects on the RAAS mean the body's fluid and salt regulation is permanently altered while the drug is present.

Aliskiren Hemifumarate carries a Black Box Warning regarding Fetal Toxicity.

• Summary: Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, Aliskiren should be discontinued as soon as possible. Exposure during the second and third trimesters is associated with fetal lung hypoplasia (underdeveloped lungs), skeletal deformations, and neonatal renal failure. Women of childbearing age should discuss effective birth control options with their healthcare providers before starting this medication.

Report any unusual symptoms or persistent side effects to your healthcare provider to ensure your treatment plan remains safe and effective.

Aliskiren Hemifumarate is a potent cardiovascular medication that requires careful oversight. Patients must be aware that while the drug effectively lowers blood pressure, it interacts significantly with the body's internal chemistry, particularly regarding potassium levels and kidney function. It is not suitable for everyone, and certain medical conditions require frequent monitoring or complete avoidance of the drug.

WARNING: FETAL TOXICITY

• When pregnancy is detected, discontinue Aliskiren as soon as possible.
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See the "Special Populations" section for more detailed information on pregnancy risks.

Allergic Reactions and Angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with Aliskiren. This is a medical emergency as it can lead to airway obstruction. Patients with a history of angioedema (regardless of the cause) may be at higher risk. If swelling occurs, the drug must be stopped immediately and emergency care sought.

Hypotension (Low Blood Pressure)

In patients with an activated renin-angiotensin system, such as those who are volume- or salt-depleted (e.g., those receiving high doses of diuretics), symptomatic hypotension may occur after starting Aliskiren. This condition should be corrected prior to administration, or the treatment should start under close medical supervision.

Impaired Renal Function

Aliskiren can cause changes in kidney function, including acute renal failure. Patients at high risk include those with pre-existing renal artery stenosis (narrowing of the arteries to the kidneys), severe heart failure, or those taking other drugs that affect the kidneys (like NSAIDs). Periodic monitoring of serum creatinine is essential.

Hyperkalemia

Aliskiren increases the risk of high blood potassium. This risk is amplified in patients with diabetes, chronic kidney disease, or those using potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium.

Patients taking Aliskiren Hemifumarate will require regular laboratory monitoring, including:

• Serum Potassium: To check for hyperkalemia.
• Serum Creatinine/BUN: To monitor kidney function.
• Blood Pressure: Regular home and office readings to ensure the dose is appropriate.

Aliskiren may cause dizziness or fatigue, especially during the first few days of treatment or after a dose increase. Patients should observe how they react to the medication before driving or operating heavy machinery.

While there is no direct chemical interaction between alcohol and Aliskiren, alcohol can enhance the blood pressure-lowering effect of the drug, potentially leading to increased dizziness, lightheadedness, or fainting. It is generally advised to limit alcohol consumption while on antihypertensive therapy.

There is no evidence of a "rebound effect" (a sudden, dangerous spike in blood pressure) when Aliskiren is stopped. However, blood pressure will eventually return to pre-treatment levels. Patients should never stop taking the medication abruptly without a plan from their doctor to transition to another therapy.

> Important: Discuss all your medical conditions, especially kidney disease, diabetes, or a history of allergic reactions, with your healthcare provider before starting Aliskiren Hemifumarate.

• ACE Inhibitors and ARBs in Patients with Diabetes: The use of Aliskiren in combination with Angiotensin-Converting Enzyme Inhibitors (e.g., Lisinopril) or Angiotensin II Receptor Blockers (e.g., Valsartan) is strictly contraindicated in patients with diabetes. This combination significantly increases the risk of non-fatal stroke, renal dysfunction, hyperkalemia, and severe hypotension.
• Cyclosporine: Concurrent use with cyclosporine (an immunosuppressant) is contraindicated. Cyclosporine significantly increases Aliskiren blood levels (up to 5-fold), which can lead to toxicity.
• Itraconazole: This potent P-glycoprotein inhibitor can significantly increase the plasma concentration of Aliskiren and should be avoided.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Drugs like ibuprofen, naproxen, and selective COX-2 inhibitors can reduce the antihypertensive effect of Aliskiren. Furthermore, in patients who are elderly, volume-depleted, or have compromised renal function, the combination may result in a further deterioration of kidney function, including possible acute renal failure.
• Potassium-Sparing Diuretics: Medications such as spironolactone, triamterene, or amiloride can lead to dangerously high potassium levels when taken with Aliskiren.
• Potassium Supplements/Salt Substitutes: These should be used only under medical supervision while taking Aliskiren.

• Furosemide: Aliskiren may reduce the peak plasma concentration and overall exposure of oral furosemide (a loop diuretic). Patients should be monitored for reduced diuretic effect.
• Atorvastatin: May slightly increase the levels of Aliskiren, though usually not enough to require a dose change.

• High-Fat Meals: As previously noted, high-fat meals dramatically decrease the absorption of Aliskiren. To maintain consistent blood pressure control, the drug must be taken consistently either with or without food.
• Grapefruit Juice: While the interaction is not as severe as with some other drugs, grapefruit juice may moderately affect the transport of Aliskiren in the gut. It is best to avoid large quantities of grapefruit juice.

• St. John’s Wort: This herbal supplement induces CYP3A4 and P-glycoprotein, which may reduce the effectiveness of Aliskiren.
• Potassium-rich herbs: Herbs like dandelion or nettle, which have diuretic properties and high potassium content, should be used with caution.

Aliskiren does not typically interfere with standard laboratory tests, but its physiological effects will be reflected in elevated serum creatinine and potassium levels, which must be interpreted in the context of the drug's mechanism.

Mechanism of Interactions

Most Aliskiren interactions occur through two pathways: the inhibition of the P-glycoprotein (P-gp) transporter (which Aliskiren is a substrate for) or pharmacodynamic synergy (where two drugs affect the same physiological system, like the RAAS, leading to over-suppression).

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking to prevent dangerous drug interactions.

There are several scenarios where Aliskiren Hemifumarate must NEVER be used due to the risk of severe harm or death:

1. 1Pregnancy: Due to the high risk of fetal toxicity, Aliskiren is absolutely contraindicated in pregnant women. It can cause renal failure and skull deformities in the fetus.
2. 2Diabetes with ACEIs/ARBs: Patients with diabetes mellitus must never take Aliskiren if they are already taking an ACE inhibitor or an ARB. The ALTITUDE trial demonstrated that this combination increases the risk of cardiovascular and renal events without providing additional benefit.
3. 3Hypersensitivity: Anyone with a known allergy to Aliskiren or any of its inactive ingredients must avoid the drug. Symptoms of hypersensitivity include rash, itching, and angioedema.
4. 4Pediatric Patients < 2 Years: The drug is contraindicated in this age group due to the risk of significant renal toxicity as the kidneys and RAAS are not yet fully developed.

These conditions require a careful risk-benefit analysis by a healthcare professional:

• Severe Renal Impairment (GFR < 30 mL/min): The risk of hyperkalemia and further renal decline is high.
• Volume Depletion: Patients who are severely dehydrated or have low salt levels should have these conditions corrected before starting Aliskiren.
• Renal Artery Stenosis: Patients with narrowing of the arteries to both kidneys (or one kidney in patients with only one) are at high risk for acute kidney failure when taking RAAS blockers.

While Aliskiren is chemically distinct from ACE inhibitors and ARBs, patients who have experienced angioedema with those classes should be monitored very closely, as there may be a predisposition to similar reactions with Aliskiren.

> Important: Your healthcare provider will evaluate your complete medical history before prescribing Aliskiren Hemifumarate.

Aliskiren is classified as a high-risk medication during pregnancy. According to the FDA, use of drugs that act on the RAAS during the second and third trimesters reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios (low amniotic fluid) can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria (failure of kidneys to produce urine), hypotension, renal failure, and death. If a patient becomes pregnant, the drug must be stopped immediately.

It is not known whether Aliskiren is excreted in human milk. However, the drug was secreted in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Aliskiren is approved for children 6 years and older. It is NOT approved for children under the age of 2. In children aged 2 to 6, safety and efficacy have not been fully established. Pediatric patients require careful monitoring of potassium and kidney function, as their physiological systems are more sensitive to RAAS manipulation.

In clinical trials, approximately 25% of patients were 65 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. However, older adults are more likely to have age-related decreases in renal function, making them more susceptible to hyperkalemia and drug-induced renal impairment. Monitoring is key.

For patients with mild to moderate renal impairment, no dose adjustment is necessary. For those with severe impairment (GFR < 30 mL/min), Aliskiren is not recommended unless the potential benefits outweigh the risks, as these patients were largely excluded from clinical trials and the risk of hyperkalemia is substantial.

Since Aliskiren is primarily eliminated through the feces and undergoes minimal hepatic metabolism, patients with liver disease (Child-Pugh A, B, or C) do not require dose adjustments. The pharmacokinetics of the drug remain relatively stable even in the presence of hepatic dysfunction.

> Important: Special populations require individualized medical assessment to ensure safety.

Aliskiren Hemifumarate is a direct renin inhibitor. Its molecular target is the enzyme renin, which is secreted by the juxtaglomerular apparatus in the kidneys. Renin is the initiator of the Renin-Angiotensin-Aldosterone System (RAAS). Aliskiren binds to the active site of renin, specifically the S3bp pocket, which is essential for its catalytic activity. By blocking this site, Aliskiren prevents renin from cleaving its only known substrate, angiotensinogen, into angiotensin I. This results in a comprehensive reduction of the entire RAAS cascade, lowering levels of angiotensin I, angiotensin II, and aldosterone, while simultaneously reducing Plasma Renin Activity (PRA).

The blood pressure-lowering effect of Aliskiren is dose-dependent within the range of 75 mg to 300 mg. Following a single dose, the onset of antihypertensive activity occurs within 1 to 2 hours, with the maximum effect reached within 3 to 6 hours. With chronic once-daily dosing, the full blood pressure-lowering effect is usually achieved within 2 weeks. Because of its long half-life, the antihypertensive effect is maintained for a full 24 hours, providing a stable trough-to-peak ratio.

| Parameter | Value |

|---|---|

| Bioavailability | ~2.5% |

| Protein Binding | 47% - 51% |

| Half-life | 24 - 40 hours |

| Tmax | 1 - 3 hours |

| Metabolism | Minimal (CYP3A4) |

| Excretion | Fecal (91%), Renal (0.6%) |

• Molecular Formula: C30H53N3O6 · 0.5 C4H4O4
• Molecular Weight: 609.8 (as hemifumarate salt)
• Solubility: Highly soluble in water and ethanol.
• Description: Aliskiren Hemifumarate is a white to slightly yellowish crystalline powder. It is a non-peptide molecule, which allows it to be orally active, unlike earlier peptide-based renin inhibitors which required injection.

Aliskiren belongs to the class of Direct Renin Inhibitors (DRIs). It is currently the only member of this class approved for the treatment of hypertension. While it shares the same ultimate goal as ACE inhibitors and ARBs (suppression of the RAAS), its unique point of intervention at the rate-limiting step distinguishes it from all other antihypertensive medications.