Ofev
Ofev
Generic Name
Ofev
Mechanism
- Competitive EGFR inhibitor – Erlotinib binds reversibly to the ATP‑binding pocket of the intracellular TK domain of the EGFR (HER‑1).
- Inhibition of phosphorylation – This blocks autophosphorylation of EGFR residues (Tyr 1068, Tyr 1173, Tyr 845) and prevents recruitment of downstream effectors such as PI3K/AKT, RAS/RAF/MEK/ERK, and STAT pathways.
- Resulting cellular effects – Decreases cell proliferation, induces apoptosis, impairs angiogenesis, and stabilizes tumor DNA repair mechanisms.
Because many EGFR‑dependent cancers have activating exon 19 deletions or L858R point mutations, erlotinib’s potency is highest in these contexts.
Pharmacokinetics
| Parameter | Details |
| Absorption | Rapid, oral; bioavailability ~55%. Peak plasma concentration (tmax) ~1 h. Absorption significantly enhanced (≈ 70%) when taken with a high‑fat meal. |
| Distribution | High protein binding (~90%) primarily to albumin and α‑1‑acid glycoprotein. Volume of distribution ~3–5 L/kg. |
| Metabolism | Extensive hepatic biotransformation via CYP3A4 (primary) with minor involvement of CYP1A1/1A2. Key metabolites include desmethyl‑erlotinib and erlotinib N‑oxide. |
| Elimination | Primarily fecal (≈ 75%); minor renal excretion (< 10%). Half‑life ~36–48 h (steady‑state ~4–5 d). |
| Drug interactions | *Inhibitors* (ketoconazole, itraconazole, clarithromycin) ↑ erlotinib AUC ≈ 2‑3× → dose reduction or close monitoring. *Inducers* (rifampin, carbamazepine, phenytoin, St. John’s wort) ↓ AUC → consider dose escalation or alternative therapy. |
| Special populations | *Hepatic impairment*: Mild‑moderate → dose 100 mg q.d.; Severe → contraindicated. *Renal impairment* → No dose adjustment—erlotinib not renally cleared. *Pregnancy* → Category X; avoid. |
Indications
| Indication | Patient population | Key regulatory details |
| Advanced/metastatic EGFR‑mutant non‑small cell lung cancer (NSCLC) | Adults with exon 19 deletion or L858R point mutation | First‑line for mutation‑positive NSCLC; second‑line after failure of chemotherapy or other TKIs. |
| Metastatic colorectal cancer (mCRC) with wild‑type KRAS | Adults after ≥ 2 prior lines of therapy (e.g., FOLFOX/FOLFIRI + bevacizumab) | FDA approved**; EMA withdrew from use; use primarily in U.S. settings. |
Contraindications
- Contraindications
- Known hypersensitivity to erlotinib or any excipient.
- Active hepatitis B infection; test *HBsAg* before therapy.
- Warnings
- Interstitial lung disease (ILD)/pulmonary toxicity – Early pulmonary symptoms may precede ILD; consider discontinuing if progressive dyspnea, cough, or hypoxemia develops.
- Hypersensitivity reactions – Severe rash, pruritus, or fatal anaphylaxis reported.
- Dermatologic toxicity – Moderate‑to‑severe maculopapular rash; may impair quality of life.
- Cardiac toxicity – Rare QTc prolongation; monitor EKG, especially with concurrent QT‑modifying drugs.
- Gastrointestinal bleeding – Diarrhea may exacerbate mucosal injury; caution with NSAIDs or anticoagulants.
Dosing
| Regimen | Administration | Notes |
| Standard dose | 150 mg orally once daily | Taken on an empty stomach (≥ 1 h before or ≥ 2 h after a meal). |
| Dose adjustment | 100 mg q.d. | If grade ≥ 2 rash or other significant toxicity. |
| Hepatic impairment | Mild/Moderate: 100 mg q.d.; Severe: contraindicated | Monitor LFTs closely (baseline, week 4, month 3). |
| Drug‑drug interactions | Avoid potent CYP3A4 inducers; may need dose adjustment for inhibitors. | Consider therapeutic drug monitoring in complex regimens. |
| Meal effects | Fatty meal ↑ exposure by ~70% → consistency in meal timing or lower dose with meal; otherwise can use low‑fat option. |
• Swallow whole; do not crush or chew tablets.
• Adherence is crucial; missing > 3 days can compromise efficacy.
Adverse Effects
| Adverse Effect | Frequency | Management |
| Cutaneous rash (maculopapular) | Up to 70 % (grade 1‑2) | Topical steroids, antihistamines; dose hold/reduce if grade ≥ 3. |
| Diarrhea | 35‑50 % | Oral rehydration, loperamide; continue therapy unless severe. |
| Stomatitis/Oral mucositis | 15‑20 % | Oral hygiene, cryotherapy. |
| Interstitial lung disease | 1‑2 % (fatality 0.5‑1 %) | Immediate discontinuation; corticosteroids or hospitalization if severe. |
| Hypertension/heritable cardiotoxicity | Rare | Baseline BP, monitor. |
| Hepatotoxicity | Elevated LFTs in ~5 % | Monitor ALT/AST; hold if > 5× ULN. |
| Nutritional deficiencies (magnesium, potassium, zinc) | Common (≤ 20 %) | Routine supplementation. |
| Serious allergic reactions | Rare | Stop immediately; treat with epinephrine. |
Monitoring
| Parameter | Frequency | Rationale |
| Complete blood count (CBC) | Baseline, every 4 weeks | Detect neutropenia, anemia. |
| Liver function tests | Baseline, every 4 weeks | Monitor hepatotoxicity. |
| Chest imaging (CXR or CT) | At baseline, then if respiratory symptoms | Screen for ILD. |
| Pulmonary function tests (spirometry) | Baseline, then every 3 months | Assess for subclinical ILD. |
| Skin examination | Every visit | Grade rash, guide therapy. |
| Blood pressure | Every visit | Detect hypertension. |
| Serum electrolytes, magnesium, potassium | Baseline, every 4 weeks | Identify deficiencies. |
Clinical Pearls
- “Start high, adjust later” – Use 150 mg daily initially; only step down to 100 mg after objective rash or grade ≥ 2 toxicity, not for prophylaxis.
- Intermittent dosing strategy – Consider “dose‑and‑hold” (150 mg for 3 days, 100 mg days 4–7) for patients with high risk of rash or when combining with multikinase inhibitors.
- Food‑drug interaction – A high‑fat meal significantly increases erlotinib exposure; if inconsistent meal timing, reduce dose to 100 mg to avoid supratherapeutic levels.
- Pulmonary vigilance – Dawn or early‑morning cough progressing to dyspnea within 2–8 weeks is red flag for ILD; discontinue immediately and assess.
- Anemia and thrombocytopenia – Less common but may emerge; if grade 3‑4 cytopenias, hold until recovery.
- Concurrent EGFR‑TKIs – Avoid overlapping with other EGFR inhibitors (e.g., gefitinib) to prevent additive toxicity.
- Renal dosing – No adjustment needed; however, avoid concomitant nephrotoxic drugs with erlotinib.
- Vaccinations – Keep patients up‑to‑date, particularly pneumococcal and influenza, due to risk of pulmonary complications.
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• Key Takeaway: *Ofev* (erlotinib) is a cornerstone EGFR‑TKI for mutation‑positive NSCLC and KRAS‑wild‑type mCRC. Optimal therapeutic outcomes hinge on meticulous dosing, vigilant monitoring for pulmonary and cutaneous toxicities, and proactive management of drug–drug interactions.