Ranitidine

Generic Name: Ranitidine
Brand Names (historical): Zantac, Ranitic, Acidex, Rani 2, Zinetac
Drug Class: H2-Receptor Antagonist (H2 blocker)
Formulations (prior to withdrawal):
– Oral tablets: 75 mg (OTC), 150 mg, 300 mg
– Oral syrup: 15 mg/mL
– Injectable solution (IM/IV): 25 mg/mL
Route of Administration: Oral, Intravenous (IV), Intramuscular (IM)

---

Current Regulatory Status

As of 2020, ranitidine has been withdrawn or suspended in most countries (including the United States, EU, UK, Canada, and others) due to contamination concerns with N-Nitrosodimethylamine (NDMA), a probable human carcinogen.

• FDA (US): Requested manufacturers to withdraw all ranitidine products from the market (April 2020)

• EMA (EU): Recommended suspension of all ranitidine medicines

• MHRA (UK): Suspended ranitidine products due to safety concerns

• Health Canada: Removed ranitidine-containing products from the market

Ranitidine is no longer widely available, and its use is strongly discouraged due to contamination risks unless obtained under special access in certain countries or under reformulated conditions.

---

Previously Approved Therapeutic Indications

Ranitidine was widely used as a gastric acid-suppressing agent. It reduced stomach acid by selectively inhibiting histamine H2 receptors on gastric parietal cells.

Approved Indications (Before Withdrawal):

1. Peptic Ulcer Disease (PUD)
   – Treatment and maintenance of duodenal and gastric ulcers
   – Healing of ulcers associated with NSAIDs

2. Gastroesophageal Reflux Disease (GERD)
   – Short-term and maintenance therapy for erosive esophagitis
   – Relief of symptoms like heartburn and acid regurgitation

3. Zollinger-Ellison Syndrome
   – Pathological hypersecretory conditions

4. Stress Ulcer Prophylaxis (in critically ill hospitalized patients)
   – IV/IM formulation used in ICUs

5. Prevention of Aspiration Pneumonitis (perioperative acid suppression)
   – Often used before anesthesia induction

6. Dyspepsia and Heartburn (OTC use)
   – Occasional relief of heartburn, sour stomach, or acid indigestion

---

Mechanism of Action

Ranitidine is a competitive and reversible antagonist of histamine H2 receptors located on gastric parietal cells.

This leads to:

• Inhibition of basal, nocturnal, and stimulated gastric acid secretion

• Reduction in both volume and concentration of gastric acid

• Less acid-related mucosal irritation and promotion of ulcer healing

Compared to proton pump inhibitors (PPIs), H2 blockers like ranitidine had a faster onset but shorter duration of action and were generally less effective for severe or long-term acid suppression.

---

Dosing and Administration (Before Market Withdrawal)

Adults:

• Duodenal or Gastric Ulcer (active):
  – 150 mg twice daily or 300 mg once daily at bedtime
  – Duration: typically 4–8 weeks

• Maintenance of Ulcer Healing:
  – 150 mg once daily at bedtime

• GERD (erosive):
  – 150 mg twice daily
  – In severe cases: up to 300 mg twice daily

• Zollinger-Ellison Syndrome:
  – Initial: 150 mg twice daily; titrate based on gastric acid output

• OTC Heartburn/Indigestion Relief:
  – 75–150 mg up to twice daily
  – Taken 30–60 minutes before food that triggers symptoms

Children (used off-label or under specialist care):

• Doses were weight-based: 2–4 mg/kg/dose twice daily (max 300 mg/day)

IV/IM (Hospital Setting):

• 50 mg every 6–8 hours or continuous infusion

• Often used for stress ulcer prophylaxis or when oral administration was not possible

---

Pharmacokinetics

• Oral Bioavailability: ~50%

• Onset of Action: ~30 minutes

• Peak Effect: 1–3 hours

• Duration of Action: 8–12 hours

• Protein Binding: ~15%

• Metabolism: Minimal hepatic metabolism

• Half-life: 2–3 hours (prolonged in renal impairment)

• Excretion: Primarily renal (unchanged drug)

Dose adjustment was necessary in patients with creatinine clearance <50 mL/min.

---

Contraindications

• Hypersensitivity to ranitidine or other H2 blockers

• History of acute porphyria (can trigger attacks)

• Avoid use in pregnancy and lactation unless clearly needed

• Due to NDMA contamination: contraindicated globally for now

---

Warnings and Precautions (Pre-Withdrawal)

1. Masking of Gastric Cancer Symptoms
   – Symptomatic relief may delay diagnosis
   – Persistent or worsening dyspepsia warranted endoscopy

2. Renal Impairment
   – Dose adjustment required
   – Risk of CNS adverse events higher in elderly with renal dysfunction

3. Hepatic Dysfunction
   – Ranitidine rarely associated with liver enzyme elevations

4. Confusional States and Hallucinations
   – More common in elderly and critically ill patients

5. Vitamin B12 Deficiency (rare)
   – Long-term use may interfere with B12 absorption

---

Adverse Effects (Prior to Withdrawal)

Common (1–10%):

• Headache

• Diarrhea or constipation

• Abdominal pain

• Nausea

• Dizziness

• Rash

Uncommon to Rare (<1%):

• Confusion, hallucinations (especially in elderly)

• Hepatitis (usually reversible)

• Bradycardia or arrhythmia (IV use)

• Gynecomastia (especially with prolonged use)

• Thrombocytopenia, leukopenia

• Interstitial nephritis

• Pancreatitis

• Stevens-Johnson syndrome

---

Drug Interactions

Ranitidine has fewer interactions than cimetidine but still interacts with some agents:

1. Warfarin:
   – Possible elevation of INR due to CYP2C9 inhibition (rare)

2. Ketoconazole, Itraconazole, Atazanavir:
   – Acid suppression reduces absorption of drugs requiring low pH

3. Glipizide/Glyburide:
   – Potential increased hypoglycemic effect (monitor)

4. Sucralfate:
   – May reduce absorption if given simultaneously; space by at least 2 hours

5. Procainamide:
   – Reduced renal clearance with ranitidine; avoid or monitor closely

---

Monitoring Parameters (During Prior Use)

• Clinical symptom resolution (heartburn, epigastric pain)

• Gastric pH (in ICU patients needing acid suppression)

• Renal function (especially in elderly)

• Liver enzymes (in long-term use or hepatic impairment)

• CBC (if unexplained bruising, infection, or fatigue)

---

NDMA Contamination and Global Withdrawal

In 2019–2020, several batches of ranitidine were found to contain NDMA, a probable human carcinogen, especially after long-term storage or exposure to high temperatures. Investigations by global regulatory authorities (FDA, EMA, MHRA) concluded:

• NDMA levels could increase over time, even under recommended storage conditions

• Manufacturers could not guarantee long-term product safety

• Safer alternatives exist (e.g., famotidine, PPIs)

As a result:
– Ranitidine was withdrawn from the market globally
– Healthcare providers were instructed to switch patients to alternative agents

---

Alternative Medications

Drug	Class	Notes
Famotidine	H2 blocker	Preferred H2 blocker replacement; no NDMA concerns
Nizatidine	H2 blocker	Structurally similar; limited availability
Omeprazole	Proton Pump Inhibitor (PPI)	More potent acid suppression
Lansoprazole	PPI	Once-daily dosing; effective for GERD
Esomeprazole	PPI	Superior acid control in severe GERD

Patient Counseling Points (If Found in Use)

• Discontinue ranitidine if still in possession; do not use outdated supplies

• Return unused medications to a pharmacy for safe disposal

• Consult your healthcare provider for alternative acid suppression therapies

• Do not switch to herbal remedies or supplements without medical advice

---

Global Regulatory Decisions

• FDA (April 2020): Full market withdrawal

• EMA (2020): Recommended suspension of all ranitidine-containing medicines

• MHRA (UK): Suspended ranitidine in all formulations

• Health Canada: All prescription and OTC ranitidine products recalled

• India: Temporary suspension; some generics reformulating under stricter NDMA limits